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Spinal cord injury (SCI) is a profound medical condition that significantly hampers motor function, imposing substantial limitations on daily activities and exerting a considerable financial burden on patients and their families. The constrained regenerative capacity of endogenous spinal cord tissue, exacerbated by the inflammatory response following the initial trauma, poses a formidable obstacle to effective therapy. Recent advancements in the field, stem cells, biomaterials, and molecular therapy, show promising outcomes. This review provides a comprehensive analysis of tissue engineering and regenerative medicine approaches for SCI treatment, including cell transplantation, tissue-engineered construct implantation, and other potential therapeutic strategies. Additionally, it sheds light on preclinical animal studies and recent clinical trials incorporating these modalities, providing a glimpse into the evolving landscape of SCI management. The investigation into spinal cord injury (SCI) treatments focuses on reducing long-term impacts by targeting scar inhibition and enhancing regeneration through stem cells, with or without growth factors. Induced pluripotent stem cells (iPSCs) show promise for autologous use, with clinical trials confirming their safety. Challenges include low cell viability and difficulty in targeted differentiation. Biomaterial scaffolds hold potential for improving cell viability and integration, and extracellular vesicles (EVs) are emerging as a novel therapy. While EV research is in its early stages, stem cell trials demonstrate safety and potential recovery. Advancing tissue engineering approaches with biomaterial scaffolds is crucial for human trials. [Display omitted] [ABSTRACT FROM AUTHOR]

Conventional alginate microcapsules are widely used for encapsulating therapeutic cells to reduce the host immune response. However, the exchange of monovalent cations with divalent cations for crosslinking can lead to a sol-gel phase transition, resulting in gradual degradation and swelling of the microcapsules in the body. To address this limitation, we present a biocompatible and nondegradable epigallocatechin-3-gallate (EGCG)-based microencapsulation with ethylamine-bridged EGCG dimers (EGCG(d)), denoted as 'Epi-Capsules'. These Epi-Capsules showed increased physical properties and Ca2+ chelating resistance compared to conventional alginate microcapsules. Horseradish peroxidase (HRP) treatment is very effective in increasing the stability of Epi-Capsule((+)HRP) due to the crosslinking between EGCG(d) molecules. Interestingly, the Epi-Capsules(oxi) using a pre-oxidized EGCG(d) can support long-term survival (>90 days) of xenotransplanted insulin-secreting islets in diabetic mice in vivo, which is attributed to its structural stability and reactive oxygen species (ROS) scavenging for lower fibrotic activity. Collectively, this EGCG-based microencapsulation can create Ca2+ chelating-resistance and anti-oxidant activity, which could be a promising strategy for cell therapies for diabetes and other diseases. Herein, a non-degradable microcapsule with pre-oxidized EGCG(d) is developed for the cell's functionality. This Epi-Capsule(oxi) shows Ca2+ chelating resistance, increased structural stability, and H 2 O 2 scavenging ability compared to alginate microcapsules. [Display omitted] • EGCG-based microencapsulation for successful cell transplantation • Ca2+ chelating-resistant Epi-Capsule(oxi) for improving degradation • H 2 O 2 scavenging effect of Epi-Capsule(oxi) • Enhanced structural stability of Epi-Capsule(oxi) • Long-term effect of Epi-Capsule(oxi) with lower degradation after implantation [ABSTRACT FROM AUTHOR]

• The therapeutic effects of different types of cell transplantation (Neural stem cells, Schwann cells, olfactory ensheathing cells and mesenchymal stem cells) in the application of NPP were discussed comprehensively. • The application value of cell transplantation in NPP clinical trial was discussed. • The problems and challenges of cell transplantation in the treatment of NPP were discussed. Nerve injury can not only lead to sensory and motor dysfunction, but also be complicated with neuropathic pain (NPP), which brings great psychosomatic injury to patients. At present, there is no effective treatment for NPP. Based on the functional characteristics of cell transplantation in nerve regeneration and injury repair, cell therapy has been used in the exploratory treatment of NPP and has become a promising treatment of NPP. In this article, we discuss the current mainstream cell types for the treatment of NPP, including Schwann cells, olfactory ensheathing cells, neural stem cells and mesenchymal stem cells in the treatment of NPP. These bioactive cells transplanted into the host have pharmacological properties of decreasing pain threshold and relieving NPP by exerting nutritional support, neuroprotection, immune regulation, promoting axonal regeneration, and remyelination. Cell transplantation can also change the microenvironment around the nerve injury, which is conducive to the survival of neurons. It can effectively relieve pain by repairing the injured nerve and rebuilding the nerve function. At present, some preclinical and clinical studies have shown that some encouraging results have been achieved in NPP treatment based on cell transplantation. Therefore, we discussed the feasible strategy of cell transplantation as a treatment of NPP and the problems and challenges that need to be solved in the current application of cell transplantation in NPP therapy. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy has shown promise in patients with late-line refractory multiple myeloma, with response rates ranging from 73 to 98%. To date, three products have been approved: Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), which are approved by the US Food and Drug Administration, the European Medicines Agency, Health Canada (ide-cel only), and Brazil ANVISA (cilta-cel only); and equecabtagene autoleucel (eque-cel), which was approved by the Chinese National Medical Products Administration. CAR T-cell therapy is different from previous anti-myeloma therapeutics with unique toxic effects that require distinct mitigation strategies. Thus, a panel of experts from the International Myeloma Working Group was assembled to provide guidance for clinical use of CAR T-cell therapy in myeloma. This consensus opinion is from experts in the field of haematopoietic cell transplantation, cell therapy, and multiple myeloma therapeutics. [ABSTRACT FROM AUTHOR]

In drug-induced liver injury, vascular endothelial progenitor cells, specifically the CD34+ cell fractions, have been found to decrease liver fibrosis and promote regeneration. However, it is unclear whether CD34+ cell transplantation has anti-fibrogenic effects on MASH, which has previously been treated effectively with anti-angiogenic therapy. We investigated the efficacy of ex vivo -expanded CD34+ cells in treating MASH livers. Diet-induced MASH mice were fed a choline-deficient, L-amino acid-defined, high-fat diet for 12 or 20 weeks, and were designated as a mild and a severe fibrosis model, respectively. Mouse bone marrow CD34+ cells were expanded for 7 days, transplanted into each mouse once or twice 2 weeks later, and sacrificed at 4 weeks after the first transplantation. Expanded CD34+ cell transplantation ameliorated liver fibrosis, regardless of fibrosis degree, as indicated by the decrease in α-smooth muscle actin-positive cells, hydroxyproline concentration, and fibrogenic gene expression of Col1a1 and Timp1. Furthermore, engrafted CD34+ cells reduced alanine transaminase levels, the number of TUNEL+ hepatocytes, and 8-OHdG concentration. RNA-sequencing data showed that "defense response to virus" was the most down-regulated category in the Gene Ontology analysis and subsequent analysis revealed the suppression of RIG-I-like receptors/Irf7/Stat1/Cxcl10 axis in expanded CD34+ cell-transplanted livers. Finally, the downregulation of CXCL10 expression inhibits the mobilization of inflammatory immune cells, macrophages, T cells, and natural killer cells to the MASH liver. These findings suggest that transplanted expanded CD34+ cells alleviate fibrotic liver injury in MASH mouse models through possible modulation of the innate immune response, which is abnormally activated by hepatocyte lipotoxicity. [ABSTRACT FROM AUTHOR]

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin fragility disorder caused by mutations in the COL7A1 gene, which encodes type VII collagen (COL7), the main constituent of anchoring fibrils for attaching the epidermis to the dermis. Persistent skin erosions frequently result in intractable ulcers in RDEB patients. Adipose-derived mesenchymal stromal cells (AD-MSCs) are easily harvested in large quantities and have low immunogenicity. Therefore, they are suitable for clinical use, including applications involving allogeneic cell transplantation. Keratinocyte-like cells transdifferentiated from AD-MSCs (KC-AD-MSCs) express more COL7 than undifferentiated AD-MSCs and facilitate skin wound healing with less contracture. Therefore, these cells can be used for skin ulcer treatment in RDEB patients. We investigated whether KC-AD-MSCs transplantation ameliorated the RDEB phenotype severity in the grafted skin of a RDEB mouse model (col7a1 -null) on the back of the immunodeficient mouse. KC-AD-MSCs were intradermally injected into the region surrounding the skin grafts, and this procedure was repeated after 7 days. After a further 7-day interval, the skin grafts were harvested. Neodeposition of COL7 and generation of anchoring fibrils at the dermal-epidermal junction were observed, although experiments were based on qualitative. KC-AD-MSCs may correct the COL7 insufficiency, repair defective/reduced anchoring fibrils, and improve skin integrity in RDEB patients. • KC-AD-MSCs are shown to be stratified and adhere each other by expressing desmosome-like structures. • KC-AD-MSCs-injected skin demonstrated predominantly suppressed blister formation. • Intradermal KC-AD-MSCs injection deposited COL7 at the dermal-epidermal junction. • KC-AD-MSCs have therapeutic potential for RDEB treatment. [ABSTRACT FROM AUTHOR]

Renal transplantation represents the foremost efficacious approach for ameliorating end-stage renal disease. Despite the current state of advanced renal transplantation techniques and the established postoperative immunosuppression strategy, a subset of patients continues to experience immune rejection during both the early and late postoperative phases, ultimately leading to graft loss. Consequently, the identification of immunobiomarkers capable of predicting the onset of immune rejection becomes imperative in order to facilitate early intervention strategies and enhance long-term prognoses. Upon reviewing the pertinent literature, we identified several indicators that could potentially serve as immune biomarkers to varying extents. These include the T1/T2 ratio, Treg/Thl7 ratio, IL-10/TNF-a ratio, IL-33, IL-34, IL-6, IL-4, other cytokines, and N0X2/4. [ABSTRACT FROM AUTHOR]

Background: Cardiac allograft rejection (AR) remains a significant complication following heart transplantation. The primary objective of our study is to gain a comprehensive understanding of the fundamental mechanisms involved in AR and identify possible therapeutic targets. Methods: We acquired the GSE87301 dataset from the Gene Expression Omnibus database. In GSE87301, a comparison was conducted on blood samples from patients with and without cardiac allograft rejection (AR and NAR) to detect differentially expressed genes (DEGs). Enrichment analysis was conducted to identify the pathways that show significant enrichment during AR. Machine learning techniques, including the least absolute shrinkage and selection operator regression (LASSO) and random forest (RF) algorithms, were employed to identify potential genes for the diagnosis of AR. The diagnostic value was evaluated using a nomogram and receiver operating characteristic (ROC) curve. Additionally, immune cell infiltration was analyzed to explore any dysrégulation of immune cells in AR. Results: A total of 114 DEGs were identified from the GSE87301 dataset. These DEGs were mainly found to be enriched in pathways related to the immune system. To identify the signature genes, the LASSO and RF algorithms were used, and four genes, namely ALAS2, HBD, EPB42, and FECH, were identified. The performance of these signature genes was evaluated using the receiver operating characteristic curve (ROC) analysis, which showed that the area under the curve (AUC) values for ALAS2, HBD, EPB42, and FECH were 0.906, 0.881, 0.900, and 0.856, respectively. These findings were further confirmed in the independent datasets and clinical samples. The selection of these specific genes was made to construct a nomogram, which demonstrated excellent diagnostic ability. Additionally, the results of the single-sample gene set enrichment analysis (ssGSEA) revealed that these genes may be involved in immune cell infiltration. Conclusion: We identified four signature genes (ALAS2, HBD, EPB42, and FECH) as potential peripheral blood diagnostic candidates for AR diagnosis. Additionally, a nomogram was constructed to aid in the diagnosis of heart transplantation. This study offers valuable insights into the identification of candidate genes for heart transplantation using peripheral blood samples. [ABSTRACT FROM AUTHOR]

Allogeneic hemopoietic cell transplantation remains the goal of therapy for high-risk acute myeloid leukemia (AML). However, treatment failure in the form of leukemia relapse or severe graft-versus-host disease remains a critical area of unmet need. Recently, significant progress has been made in the cell therapy-based interventions both before and after transplant. In this review, the Stem Cell Engineering Committee of the International Society for Cell and Gene Therapy summarizes the literature regarding the identification of high risk in AML, treatment approaches before transplant, optimal transplant platforms and measures that may be taken after transplant to ideally prevent, or, if need be, treat AML relapse. Although some strategies remain in the early phases of clinical investigation, they are built on progress in pre-clinical research and cellular engineering techniques that are already improving outcomes for children and adults with high-risk malignancies. [ABSTRACT FROM AUTHOR]

Allogeneic haematopoietic cell transplant (allo-HCT) recipients who are cytomegalovirus (CMV)-seronegative have better post-transplant outcomes than CMV-seropositive recipients. Letermovir (LTV) is approved for CMV primary prophylaxis in adults who are CMV-seropositive after allo-HCT, and its use is associated with improved long-term post-transplant outcomes. We analysed whether LTV has affected the relationship between CMV serostatus and post-transplant outcomes. We conducted a retrospective single-centre cohort study of allo-HCT recipients, stratified according to donor (D) and recipient (R). CMV serostatus and the use of LTV: D−/R−, R+/LTV−, and R+/LTV+. Outcomes measured were all-cause and non-relapse mortality, clinically significant CMV infection, graft-versus-host disease, and relapse up to week 48 after allo-HCT. The D−/R− group served as the reference for comparisons in univariate, competing risk regression, and cumulative incidence functions. The analysis included 1071 consecutive allo-HCT recipients: 131 D−/R−, 557 R+/LTV−, and 383 R+/LTV+. All-cause mortality by day 100 was 6.1% for the D−/R− group, compared with 14.0% (p 0.024) and 7.8% (p 0.7) for the R+/LTV− and R+/LTV + groups, respectively. Non-relapse mortality by day 100 was 11.0%, 6.8% and 3.8% for R+/LTV−, R+/LTV+, and D−/R− groups, respectively, without significant difference. When including relapse as a competing event, the hazard ratio for non-relapse mortality was 1.83 (95% CI: 1.12–2.99, p 0.017) for R+/LTV− compared with D−/R− and 1.05 (95% CI 0.62–1.77, p 0.85) for R+/LTV + compared with D−/R−. CMV primary prophylaxis with LTV abrogated the mortality gap based on CMV serostatus, a protective effect that persisted after discontinuation of primary prophylaxis. [ABSTRACT FROM AUTHOR]

Stem cells are recognized as an important target and tool in regenerative engineering. In this study, we explored the feasibility of engineering amniotic fluid-derived mesenchymal stem cell-secreted molecules (afMSC-SMs) as a versatile bioactive material for skin regenerative medicine applications in a time- and cost-efficient and straightforward manner. afMSC-SMs, obtained in powder form through ethanol precipitation, effectively contributed to preserving the self-renewal capacity and differentiation potential of primary human keratinocytes (pKCs) in a xeno -free environment, offering a potential alternative to traditional culture methods for their long-term in vitro expansion, and allowed them to reconstitute a fully stratified epithelium sheet on human dermal fibroblasts. Furthermore, we demonstrated the flexibility of afMSC-SMs in wound healing and hair regrowth through injectable hydrogel and nanogel-mediated transdermal delivery systems, respectively, expanding the pool of regenerative applications. This cell-free approach may offer several potential advantages, including streamlined manufacturing processes, scalability, controlled formulation, longer shelf lives, and mitigation of risks associated with living cell transplantation. Accordingly, afMSC-SMs could serve as a promising therapeutic toolbox for advancing cell-free regenerative medicine, simplifying their broad applicability in various clinical settings. [Display omitted] [ABSTRACT FROM AUTHOR]

The success of mRNA vaccines against COVID-19 has enhanced the potential of lipid nanoparticles (LNPs) as a system for the delivery of mRNA. In this review, we describe our progress using a lipid library to engineer ionizable lipids and promote LNP technology from the viewpoints of safety, controlled biodistribution, and mRNA vaccines. These advancements in LNP technology are applied to cancer immunology, and a potential nano-DDS is constructed to evaluate immune status that is associated with a cancer-immunity cycle that includes the sub-cycles in tumor microenvironments. We also discuss the importance of the delivery of antigens and adjuvants in enhancing the cancer-immunity cycle. Recent progress in NK cell targeting in cancer immunotherapy is also introduced. Finally, the impact of next-generation DDS technology is explained using the MITO-Porter membrane fusion-based delivery system for the organelle targeting of the mitochondria. We introduce a successful example of the MITO-Porter used in a cell therapeutic strategy to treat cardiomyopathy. [Display omitted] • The efficiency of lipid nanoparticles is discussed from the viewpoint of a 3-dimensinal structure of ionizable lipids. • A potential nano-DDS is designed based on a cancer immunity cycle that includes sub-cycles in a tumor microenvironment. • MITO-Porter was introduced as an organelle-targeting DDS that was successfully applied to cell transplantation therapy. [ABSTRACT FROM AUTHOR]

Pelizaeus–Merzbacher disease (PMD) is a fatal leukodystrophy characterized by selective loss of myelinating oligodendrocytes due to misfolded proteolipid protein (PLP). The oligodendrocyte-specific pathology of PMD makes it attractive for testing novel myelin-restoring therapeutic technologies. Several newer-generation therapies will be trialed in PMD patients in the near term, including RNA-suppressive therapy using antisense oligonucleotides, and glial progenitor cell transplantation. These technologies may have broader applications for additional myelin disorders, including multiple sclerosis and other leukodystrophies. Endoplasmic reticulum (ER) stress contributes to the pathology in several central and peripheral myelin disorders, including PMD. ER stress modulators have shown efficacy in preclinical PMD models, and curcumin was recently tested in PMD patients, with results pending. Pelizaeus–Merzbacher disease (PMD) is caused by mutations in the proteolipid protein 1 (PLP1) gene encoding proteolipid protein (PLP). As a major component of myelin, mutated PLP causes progressive neurodegeneration and eventually death due to severe white matter deficits. Medical care has long been limited to symptomatic treatments, but first-in-class PMD therapies with novel mechanisms now stand poised to enter clinical trials. Here, we review PMD disease mechanisms and outline rationale for therapeutic interventions, including PLP1 suppression, cell transplantation, iron chelation, and intracellular stress modulation. We discuss available preclinical data and their implications on clinical development. With several novel treatments on the horizon, PMD is on the precipice of a new era in the diagnosis and treatment of patients suffering from this debilitating disease. [ABSTRACT FROM AUTHOR]

Despite advancements in wound care, wound healing remains a challenge, especially in individuals with type 2 diabetes. Cell sheet technology has emerged as an efficient and promising therapy for tissue regeneration and wound repair. Among these, bilayered human keratinocyte-fibroblast cell sheets constructed using temperature-responsive culture surfaces have been shown to mimic a normal tissue-like structure and secrete essential cytokines and growth factors that regulate the wound healing process. This study aimed to evaluate the safety and therapeutic potential of human skin cell sheets to treat full-thickness skin defects in a rat model of type 2 diabetes. Our findings demonstrate that diabetic wounds transplanted with bilayered cell sheets resulted in accelerated re-epithelialization, increased angiogenesis, enhanced macrophage polarization and regeneration of tissue that closely resembled healthy skin. In contrast, the control group that did not receive cell sheet transplantation presented characteristic symptoms of impaired and delayed wound healing associated with type 2 diabetes. The secretory cytokines and the upregulation of Nrf2 expression in response to cell sheet transplantation are believed to have played a key role in the improved wound healing observed in diabetic rats. Our study suggests that human keratinocyte-fibroblast cell sheets hold great potential as a therapeutic alternative for diabetic ulcers. [ABSTRACT FROM AUTHOR]

• This study demonstrated a significant inverse correlation between donor age and natural killer cell activity. • Liver-resident natural killer cells have potent antitumor activity. • Useful information was found for cell therapy in liver transplantation. Natural killer (NK) cells are involved in innate immunity and have been reported to play an important role in hepatocellular carcinoma recurrence and post-liver transplantation (LT) infection. However, the relationship between donor age and liver-resident NK cell activity remains to be elucidated. We successfully performed NK cell immunotherapy in 19 living donor LT recipients to prevent post-LT bloodstream infections. Liver mononuclear cells (LMNCs) were collected from the liver graft perfusate and stimulated with interleukin 2 for 3 days. Liver-resident NK cells were analyzed using flow cytometry and a chromium release assay before and after cell culture. The median donor age was 44 years (range, 24-64 years). The graft weight was 492 g (range, 338-642 g), and the median number of LMNCs was 584 million cells (range, 240-1472 million cells). The proportion of NK cells before and after culture was 22% and 33%, respectively. A significant correlation was found between graft weight and the number of LMNCs. However, no correlation was found between donor age and the number or percentage of NK cells in the liver. Moreover, donor age showed a significant inverse correlation with NKp46 and NKp44 expression before culture and with NKp44, tumor necrosis factor-related apoptosis-inducing ligand, and CD69 expression after culture. A significant inverse correlation was observed between donor age and NK cell activity in the liver. This information may be useful for cell therapy during LT. [ABSTRACT FROM AUTHOR]

The brain is not immune privileged, leading to new challenges for cell therapies. While cell therapies for stroke have been shown to enhance recovery in animal studies, their move into clinical reality needs to be reassessed from an immunological perspective. A major hurdle in allogeneic cell transplantation is the low immunocompatibility due to human leukocyte antigen (HLA) mismatches. Finding an HLA match for unrelated individuals is 1 in 100 000, and hundreds of homozygous cell lines are needed for most of the population. Modifying HLAs and related genes in cell grafts has improved immune compatibility in animal studies, setting the stage for human trials. HLA engineering offers a means to bypass the host immune response and reduce cells required for the HLA spectrum. However, these cell sources introduce safety challenges, addressed with genetic safety mechanisms. Stem cell therapy is an emerging treatment paradigm for stroke patients with remaining neurological deficits. While allogeneic cell transplants overcome the manufacturing constraints of autologous grafts, they can be rejected by the recipient's immune system, which identifies foreign cells through the human leukocyte antigen (HLA) system. The heterogeneity of HLA molecules in the human population would require a very high number of cell lines, which may still be inadequate for patients with rare genetic HLAs. Here, we outline key progress in genetic HLA engineering in pluripotent stem and derived cells to evade the host's immune system, reducing the number of allogeneic cell lines required, and examine safety measures explored in both preclinical studies and upcoming clinical trials. [ABSTRACT FROM AUTHOR]

Cell transplantation is a promising therapeutic strategy for myocardial regeneration therapy. To improve therapeutic effects, we developed a culture medium additive that enhances the mitochondrial function of cardiomyocytes for transplantation. A mitochondrial targeting drug delivery system (MITO-Porter system) was used to deliver mitochondrial activation molecules to mouse-derived cardiac progenitor cells. In this study, we investigated whether the mitochondrial function of human-derived myocardial precursor cells could be enhanced using MITO-Porter. Human cardiosphere-derived cells (CDCs) were isolated from myocardium which was excised during surgery for congenital heart disease. MITO-Porter was added to the cell culture medium to generate mitochondrial activated CDCs (human MITO cells). The human MITO cells were transplanted into myocardial ischemia-reperfusion model rat, and the effect was investigated. The transplanted human MITO cells improved the cardiac function and suppressed myocardial fibrosis compared to conventional cell transplantation methods. These effects were observed not only with myocardial administration but also by intravenous administration of human MITO cells. This study is the first study that assessed whether the mitochondrial delivery of functional compounds improved the outcome of human-derived myocardial cell transplantation therapy. [Display omitted] • Myocardial regeneration therapy is a promising treatment for heart failure. • Cell transplantation can be a treatment option used in myocardial regenerative therapy. • Mitochondrial delivery of coenzyme Q 10 to transplanted cells improves cell function. • Activating mitochondrial function increases the effect of cell transplantation. [ABSTRACT FROM AUTHOR]

Hepatic tissue engineering has been applied for the treatment of intractable liver diseases, and hepatocyte sheets are promising for this purpose. However, hepatocyte sheets have poor survival after transplantation because of their high metabolic activity. In this study, we aimed to develop basic fibroblast growth factor (bFGF)-releasing nanoparticles to prolong the survival of hepatocyte sheets after transplantation. The nanoparticles were prepared by electrospraying a bFGF-dispersed poly(D, l -lactide- co -glycolide) emulsion. bFGF-loaded PLGA nanoparticles can be developed by optimizing the applied electrospray voltage and the oil:water ratio of the emulsion. The prepared nanoparticles exhibited prompt release at the initial duration and continuous gradual release at the subsequent duration. Hepatocyte sheet engraftment was evaluated by transplanting hepatocyte sheets containing the prepared nanoparticles into rats. The hepatocyte sheets with the prepared nanoparticles exhibited longer survival than those without the bFGF nanoparticles or solution owing to the local and continuous release of bFGF from the nanoparticles and the subsequent enhanced angiogenesis at the transplantation site. These results indicated that the prepared bFGF-releasing nanoparticles can enhance the efficiency of hepatocyte sheet transplantation. The developed bFGF-releasing nanoparticles would be useful for the transplantation of cellular tissue with post-transplantation survival challenges. [Display omitted] [ABSTRACT FROM AUTHOR]

• hPMSCs transplantation rescued apoptosis after HI. • hPMSCs transplantation rescued long-term neurological ability after HI. • hPMSCs downregulated Sema 3A/NRP-1 after HI to rescued apoptosis. • Downregulated Sema 3A/NRP-1 led to the activation of PI3K/Akt/mTOR pathway. Neonatal hypoxic-ischemic encephalopathy (HIE) is an abnormal neurological condition caused by hypoxic-ischemic damage during the perinatal period. Human placenta derived mesenchymal stem cells (hPMSCs) have been shown to have protective and reparative effects in various neurological diseases; however, the research on HIE is insufficient. This study aimed to establish a rat model of HIE and transplant hPMSCs through the lateral ventricle after hypoxic-ishcemic (HI) brain damage to observe its protective effects and mechanisms, with a focus on brain apoptosis compared among groups. Differentially expressed apoptosis-related proteins were screened using a rat cytokine array and subsequent verification. Neuropilin-1 (NRP-1) and Semaphorin 3A (Sema 3A) were selected for further investigation. Western blotting was used to quantify the expression of Sema 3A and the proteins related to PI3K/Akt/mTOR signaling pathway. Exogenous Sema 3A was added to evaluate the effects of Sema 3A/NRP-1 on hPMSCs following HI injury. hPMSCs transplantation ameliorated HI-induced pathological changes, reduced apoptosis, and improved long-term neurological prognosis. Furthermore, Sema 3A/NRP-1 was a key regulator in reducing HI-induced apoptosis after hPMSCs transplantation. hPMSCs inhibited the expression of Sema 3A/NRP-1 and activated the PI3K/Akt/mTOR signaling pathway. Additionally, exogenous Sema 3A abolished the protective effects of hPMSCs against HI. In conclusion, hPMSCs transplantation reduced apoptosis and improved long-term neurological prognosis after HI by downregulating Sema 3A/NRP-1 expression and activating the PI3K/Akt/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

[Display omitted] This review summarizes recent progress at the confluence of structural biomaterials research and synthetic biology, focusing on biomedical applications involving programmed mammalian cells and bacterial cells. Synthetic biology, which aims to build genetic circuits and bottom-up synthetic networks in microbial and mammalian cells, can benefit greatly from the bio-activity and encapsulation and delivery abilities of structural biomaterials, which can facilitate gene transfection and control of gene switches, as well as cell cultivation and transplantation. Conversely, genetically engineered cells can play roles in the synthesis and modification of structural biomaterials. We discuss the opportunities opened up by this multi-disciplinary interplay, as well as the challenges facing the application of these capabilities for the development of next-generation diagnostic and therapeutic tools. [ABSTRACT FROM AUTHOR]

We conducted this phase I, open-label safety and feasibility trial of autologous cord blood (CB) stem cell (CBSC) therapy via a novel blood cardioplegia-based intracoronary infusion technique during the Norwood procedure in neonates with an antenatal diagnosis of hypoplastic left heart syndrome (HLHS). CBSC therapy may support early cardiac remodeling with enhancement of right ventricle (RV) function during the critical interstage period. Clinical grade CB mononucleated cells (CBMNCs) were processed to NetCord-FACT International Standards. To maximize yield, CBSCs were not isolated from CBMNCs. CBMNCs were stored at 4 °C (no cryopreservation) for use within 3 days and delivered after each cardioplegia dose (4 × 15 mL). Of 16 patients with antenatal diagnosis, 13 were recruited; of these 13 patients, 3 were not treated due to placental abruption (n = 1) or conditions delaying the Norwood for >4 days (n = 2) and 10 received 644.9 ± 134 × 106 CBMNCs, representing 1.5 ± 1.1 × 106 (CD34+) CBSCs. Interstage mortality was 30% (n = 3; on days 7, 25, and 62). None of the 36 serious adverse events (53% linked to 3 deaths) were related to CBMNC therapy. Cardiac magnetic resonance imaging before stage 2 (n = 5) found an RV mass index comparable to that in an exact-matched historical cohort (n = 22), with a mean RV ejection fraction of 66.2 ± 4.5% and mean indexed stroke volume of 47.4 ± 6.2 mL/m2 versus 53.5 ± 11.6% and 37.2 ± 10.3 mL/m2, respectively. All 7 survivors completed stage 2 and are alive with normal RV function (6 with ≤mild and 1 with moderate tricuspid regurgitation). This trial demonstrated that autologous CBMNCs delivered in large numbers without prior cryopreservation via a novel intracoronary infusion technique at cardioplegic arrest during Norwood palliation on days 2 to 3 of life is feasible and safe. [ABSTRACT FROM AUTHOR]

Induced pluripotent stem cells have been shown to survive, re-innervate the striatum, and relieve motor function for up to 2 years in nonhuman primates. CRISPR-Cas9-guided gene editing targeting diabetes-related genes resulted in restored β cell function and diabetes reversal in preclinical models. Autologous hematopoietic stem cell transplantation provides a possible cure for sickle cell disease and β-thalassemia. Successful clinical trials led to six FDA-approved chimeric antigen receptor-modified T cell therapies. Alum-tethered IL-12 demonstrated >400-fold greater retention in the local microenvironment for up to 6 days compared with a non-tethered cytokine counterpart. Programmed cell death 1 (PD-1) ligand chimeric with core streptavidin-presenting microgels led to an increase in the expression of genes encoding regulatory factors such as FoxP3, Ccr4, and PD-1, promoting a tolerogenic microenvironment, and allowed long-term allogeneic graft survival. Localized immunomodulation technologies are rapidly emerging as a new modality with the potential to revolutionize transplantation of cells and organs. In the past decade, cell-based immunomodulation therapies saw clinical success in the treatment of cancer and autoimmune diseases. In this review, we describe recent advances in engineering solutions for the development of localized immunomodulation techniques focusing on cellular and organoid transplantation. We begin by describing cell transplantation and highlighting notable clinical successes, particularly in the areas of stem cell therapy, chimeric antigen receptor (CAR)-T cell therapy, and islet transplantation. Next, we detail recent preclinical studies centered on genome editing and biomaterials to enhance localized immunomodulation. We close by discussing future opportunities to improve clinical and commercial success using these approaches to facilitate long-term immunomodulation technologies. [ABSTRACT FROM AUTHOR]

Thanks to their immunomodulatory, tissue-protective and regenerative properties, mesenchymal stromal cells (MSCs) are a promising approach for amyotrophic lateral sclerosis (ALS); however, trials are limited and few follow-up studies have been published. This post-hoc analysis aims to describe the potential long-term effects of MSCs in ALS, analyzing data from two phase 1 clinical trials in ALS patients conducted by our group in 2002 and 2006. We conducted two consecutive phase 1 prospective, open, pilot clinical trials, enrolling a total of 19 ALS patients. We followed patients for the duration of the disease. For each patient, we used the European Network to Cure ALS (ENCALS) survival prediction model to retrospectively calculate the expected survival at diagnosis. We then compared the predicted disease duration with the observed survival, analyzing patients at a single-patient level. Using the ENCALS model, we predicted short survival in one patient, intermediate survival in three patients, long survival in three patients and very long survival in 12 patients. The difference between predicted and observed survival for the whole group was significant and demonstrated a mean predicted survival of 70.79 months (standard deviation [SD], 27.53) and a mean observed survival of 118.8 months (SD, 89.26) (P = 0.016). Based on the monthly ALS Functional Rating Scale–Revised progression rate (median, 0.64/month), we considered 10 of 19 patients slow progressors and nine of 19 patients fast progressors. Of the slow progressors, eight of 10 (80%) had significantly increased disease duration compared with predicted, and only two (20%) had decreased estimated disease duration. By contrast, five of nine (55%) fast progressors had increased disease duration, whereas four (45%) had decreased disease duration. To date, four patients are still alive. The current study represents the first very long-term analysis of survival as an effect of MSC focal transplantation in the central nervous system of ALS patients, demonstrating that MSC transplantation could potentially slow down ALS progression and improve survival. Due to the interindividual variability in clinical course, at the current state of our knowledge, we cannot generalize the results, but these data provide new insights for planning the next generation of efficacy MSC clinical trials in ALS. [ABSTRACT FROM AUTHOR]

To confirm the efficacy and safety of Good Manufacturing Practice (GMP)-compliant autologous cultivated limbal epithelial cell sheets in government-controlled clinical trials that adhered to Good Clinical Practice stipulations for patients with unilateral limbal stem cell deficiency (LSCD). A prospective, multicenter, open-label, uncontrolled, single-arm clinical trial. Ten consecutive eyes of 10 patients with unilateral LSCD were followed for 2 years after surgery. Preoperative LSCD stage was IIB in 4 eyes and III in 6 eyes. A limbal tissue biopsy was obtained from the healthy eye, after which limbal stem cells were dissociated and cultivated on temperature-responsive culture surfaces. All cell sheets were fabricated in a GMP-grade facility under established standard operating procedures. Cell sheets were evaluated using defined shipment criteria before transplantation, and only those that met the criteria were used. The cell sheet was transplanted onto each of the patients' diseased eye after removing the conjunctival scar tissue that covered the corneal surface. The severity of LSCD was determined according to a staging method agreed on by global consensus, with eyes evaluated as being in stages IA–C representing successful corneal epithelial reconstruction. Diagnosis and staging of LSCD were determined by the trial's Eligibility Judgment Committee and Effect Assessment Committee using slit-lamp photographs including fluorescein staining. Both committees comprised 2 or 3 third-party cornea specialists, who were provided with information anonymously and randomly. Corneal epithelial reconstruction rate was the primary end point. Corneal epithelial reconstruction was successful in 6 of 10 eyes (60%) 1 year postoperatively and was significantly higher than the 15% clinically significant efficacy rate achieved by allogeneic limbal transplantation. The reconstruction rate was 70% of eyes 2 years postoperatively. Additionally, improvements in visual acuity were noted in 50% and 60% of eyes at 1 and 2 years, respectively. No clinically significant transplantation-related adverse events were observed. The efficacy and safety of cultivated limbal epithelial cell sheet transplantation were thus confirmed, and the cell sheet, named "Nepic," is now approved as a cellular and tissue-based product in Japan. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Proprietary or commercial disclosure may be found after the references. [ABSTRACT FROM AUTHOR]

Several studies have reported that mesenchymal stromal cells (MSCs) may improve neurological functions in patients with spinal cord injury (SCI). In this study, we conducted a systematic review and meta-analysis to summarize the effects of MSC treatment on different degrees of severity of SCI. Systematic searching of studies reporting outcomes of MSCs on specific injury severities of patients with SCI was performed in The National Library of Medicine (MEDLINE), Embase and Cochrane for published articles up to the 6 July 2022. Two investigators independently reviewed the included studies and extracted the relevant data. The standardized mean differences of American Spinal Injury Association (ASIA) motor score, ASIA light touch scores, ASIA pinprick scores and the Barthel index between baseline and follow-ups were pooled. A total of eight studies were included. A large majority focused on patients with ASIA grade A classification. The pooled mean differences of ASIA motor scores, ASIA light touch scores, ASIA pinprick scores and the Barthel index were –2.78 (95% confidence interval [CI] –5.12 to –0.43, P = 0.02), –18.26 (95% CI –26.09 to –10.43, P < 0.01), –17.08 (95% CI –24.10 to –10.07, P < 0.01) and –4.37 (95% CI –10.96 to 2.22, P = 0.19), respectively. MSC transplantation was a significantly effective therapy for patients with SCI with ASIA grade A. In the future, further studies are warranted to confirm the potential beneficial effects of MSC therapy. [ABSTRACT FROM AUTHOR]

Over the past two decades, developments in regenerative medicine in gastroenterology have been greatly enhanced by the application of stem cells, which can self-replicate and differentiate into any somatic cell. The discovery of induced pluripotent stem cells has opened remarkable perspectives on tissue regeneration, including their use as a bridge to transplantation or as supportive therapy in patients with organ failure. The improvements in DNA manipulation and gene editing strategies have also allowed to clarify the physiopathology and to correct the phenotype of several monogenic diseases, both in vivo and in vitro. Further progress has been made with the development of three-dimensional cultures, known as organoids, which have demonstrated morphological and functional complexity comparable to that of a miniature organ. Hence, owing to its protean applications and potential benefits, cell and organoid transplantation has become a hot topic for the management of gastrointestinal diseases. In this review, we describe current knowledge on cell therapies in hepatology and pancreatology, providing insight into their future applications in regenerative medicine. [ABSTRACT FROM AUTHOR]

Patients with hematologic malignancies are considered at high risk for COVID-19 infection either from the disease or the treatment. Hematopoietic stem cell transplantation, one of the approved therapies for hematologic malignancies, was performed worldwide during the COVID-19 era with some regulations, such as COVID-19 testing, before proceeding with transplantation or cellular therapy. To the authors' knowledge, none have reported the result of autologous hematopoietic stem cell transplantation in an active COVID-19 patient. We describe a successful clinical course of autologous bone marrow transplantation for 2 lymphoma patients who tested positive for COVID-19. A thorough discussion was conducted between multidisciplinary hemato-oncology, intensive care, and infectious diseases teams. The decision was to proceed toward bone marrow transplantation with some modifications in the transplantation protocol and close patient monitoring. Our cases lend credence that successful autologous bone marrow transplantation is possible among active COVID-19 patients. The obstacles we faced could be overcome with collaboration between a highly qualified multidisciplinary team. Despite the potential complications, the benefits of bone marrow transplantation among patients with a high risk of relapse and who are still COVID-19-positive outweigh the risks. However, further studies are still recommended to support our inference. [ABSTRACT FROM AUTHOR]

Cellular therapies are poised to transform the field of medicine. These therapies can potentially impact on cancer, regenerative medicine, and immune disorders. Cellular therapies encompass stem or non-stem cells derived from autologous, allogeneic, or xenogeneic sources. A new generation of innovative immunomodulatory interventions may accelerate translation or maximize the prospects of improving therapeutic outcomes of cellular therapies for long-term clinical success. Cellular therapies are poised to transform the field of medicine by restoring dysfunctional tissues and treating various diseases in a dynamic manner not achievable by conventional pharmaceutics. Spanning various therapeutic areas inclusive of cancer, regenerative medicine, and immune disorders, cellular therapies comprise stem or non-stem cells derived from various sources. Despite numerous clinical approvals or trials underway, the host immune response presents a critical impediment to the widespread adoption and success of cellular therapies. Here, we review current research and clinical advances in immunomodulatory strategies to mitigate immune rejection or promote immune tolerance to cellular therapies. We discuss the potential of these immunomodulatory interventions to accelerate translation or maximize the prospects of improving therapeutic outcomes of cellular therapies for clinical success. [ABSTRACT FROM AUTHOR]

Mitochondrial diseases are a group of inherited or acquired metabolic disorders caused by mitochondrial dysfunction which may affect almost all the organs in the body and present at any age. However, no satisfactory therapeutic strategies have been available for mitochondrial diseases so far. Mitochondrial transplantation is a burgeoning approach for treatment of mitochondrial diseases by recovery of dysfunctional mitochondria in defective cells using isolated functional mitochondria. Many models of mitochondrial transplantation in cells, animals, and patients have proved effective via various routes of mitochondrial delivery. This review presents different techniques used in mitochondrial isolation and delivery, mechanisms of mitochondrial internalization and consequences of mitochondrial transplantation, along with challenges for clinical application. Despite some unknowns and challenges, mitochondrial transplantation would provide an innovative approach for mitochondrial medicine. This review presents different techniques used in mitochondrial isolation and delivery, mechanisms of mitochondrial internalization and consequences of mitochondrial transplantation, along with challenges for clinical application. [Display omitted] [ABSTRACT FROM AUTHOR]

Pilot clinical trials have shown the safety of intra-arterial bone marrow mononuclear cells (BMMNCs) in stroke. However, the efficacy of different doses of intra-arterial BMMNCs in patients with acute stroke has not been tested in a randomised clinical trial. We aimed to show safety and efficacy of two different doses of autologous intra-arterial BMMNC transplantation in patients with acute stroke. The IBIS trial was a multicentre phase 2, randomised, controlled, investigator-initiated, assessor-blinded, clinical trial, in four stroke centres in Spain. We included patients (aged 18–80 years) with a non-lacunar, middle cerebral artery ischaemic stroke within 1–7 days from stroke onset and with a National Institutes of Health Stroke Scale score of 6–20. We randomly assigned patients (2:1:1) with a computer-generated randomisation sequence to standard of care (control group) or intra-arterial injection of autologous BMMNCs at one of two different doses (2 × 106 BMMNCs/kg or 5 × 106 BMMNCs/kg). The primary efficacy outcome was the proportion of patients with modified Rankin Scale scores of 0–2 at 180 days in the intention-to-treat population, comparing each BMMNC dose group and the pooled BMMNC group versus the control group. The primary safety endpoint was the proportion of serious adverse events. This trial was registered at ClinicalTrials.gov , NCT02178657 and is completed. Between April 1, 2015, and May 20, 2021, we assessed 114 patients for eligibility. We randomly assigned 77 (68%) patients: 38 (49%) to the control group, 20 (26%) to the low-dose BMMNC group, and 19 (25%) the high-dose BMMNC group. The mean age of participants was 62·4 years (SD 12·7), 46 (60%) were men, 31 (40%) were women, all were White, and 63 (82%) received thrombectomy. The median NIHSS score before randomisation was 12 (IQR 9–15), with intra-arterial BMMNC injection done a median of 6 days (4–7) after stroke onset. The primary efficacy outcome occurred in 14 (39%) patients in the control group versus ten (50%) in the low-dose group (adjusted odds ratio 2·08 [95% CI 0·55–7·85]; p=0·28), eight (44%) in the high-dose group (1·89 [0·52–6·96]; p=0·33), and 18 (47%) in the pooled BMMNC group (2·22 [0·72–6·85]; p=0·16). We found no differences in the proportion of patients who had adverse events or dose-related events, but two patients had a groin haematoma after cell injection in the low-dose BMMNC group. Intra-arterial BMMNCs were safe in patients with acute ischaemic stroke, but we found no significant improvement at 180 days on the mRS. Further clinical trials are warranted to investigate whether improvements might be possible at different timepoints. Instituto de Salud Carlos III co-funded by the European Regional Development Fund/European Social Fund, Mutua Madrileña, and the Regional Ministry of Health of Andalusia. [ABSTRACT FROM AUTHOR]

Bone marrow-derived hematopoietic stem cell transplantation/hematopoietic progenitor cell transplantation (HSCT/HPCT) is widely used and one of the most useful treatments in clinical practice. However, the homing rate of hematopoietic stem cells/hematopoietic progenitor cells (HSCs/HPCs) by routine cell transfusion is quite low, influencing hematopoietic reconstitution after HSCT/HPCT. The authors developed a micro-living motor (MLM) strategy to increase the number of magnetically empowered bone marrow cells (ME-BMCs) homing to the bone marrow of recipient mice. In the in vitro study, migration and retention of ME-BMCs were greatly improved in comparison with non-magnetized bone marrow cells, and the biological characteristics of ME-BMCs were well maintained. Differentially expressed gene analysis indicated that ME-BMCs might function through gene regulation. In the in vivo study, faster hematopoietic reconstitution was observed in ME-BMC mice, which demonstrated a better survival rate and milder symptoms of acute graft-versus-host disease after transplantation of allogeneic ME-BMCs. This study demonstrated that ME-BMCs serving as MLMs facilitated the homing of HSCs/HPCs and eventually contributed to earlier hematopoietic reconstitution in recipients. These data might provide useful information for other kinds of cell therapies. The authors performed hematopoietic stem/progenitor cell transplantation using magnetically empowered bone marrow cells (ME-BMCs) as a micro-living motor strategy. In vitro experiments showed that ME-BMCs can be manipulated under certain magnetic fields with little cytotoxicity. In vivo experiments showed that the ME-BMC strategy helped to achieve faster reconstitution in both autologous and allogeneic models. Transcriptome analysis indicated that ME-BMCs may function via not only physical forces but also gene regulation. [Display omitted] [ABSTRACT FROM AUTHOR]

Transplantation-based cell therapy holds the potential to offer sustained and physiological repair for neurological diseases and injuries, which requires the integration of transplanted neurons into the neural circuits of the human brain. Recent studies involving transplantation of human pluripotent stem cell–derived neural progenitors into the brain of model animals reveal the remarkable capacity of grafted immature human neurons to mature, project axons in a long distance, and form both pre- and postsynaptic connections with host neurons, corresponding to functional recovery. Strikingly, this circuit integration depends largely on the identity of the transplanted cells and may be modified by external stimuli. This realization begs for enriched authentic target cells for transplantation and combination with rehabilitation for better therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury occurs in a relatively large proportion of trauma patients, in whom it generally results in severe functional impairment and permanent disability. At present, however, there are no effective treatments available. Studies have shown that Schwann cells play an indispensable role in removing myelin debris and guiding axonal regeneration, and transplantation using autologous Schwann cells has shown good efficacy for patients with peripheral nerve injury. In recent years, Schwann cell autologous transplantation therapy has become an area of intensive research and is anticipated to provide a new strategy for the clinical treatment of peripheral nerve injury. In this article, we review the rationale for selecting Schwann cell autotransplantation therapy and the latest progress in key aspects of cell transplantation and clinical efficacy, and also summarize the future directions of research on this therapy. All of the above provide a strong basis for the further improvement and clinical promotion of this therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

• This is one of the largest cohorts of renal dysfunction nephrectomy patients. • Renal dysfunction patients had similar tumor histology to control patients. • Tumor histology did not vary between ESRD and renal transplant patients. Renal transplantation and end-stage renal disease are increasingly common. Renal dysfunction and immunosuppression are two risk factors in the development of renal cell carcinoma. Carcinomas in these patients are thought to be more indolent, however data are limited and mixed. Our objective was to describe the histology of resected tumors from the transplant and renal dysfunction population and compare them to a control population. This was a single-center retrospective cohort study of all patients who had a nephrectomy for a renal mass from 2009 to 2019. All transplant status and end-stage renal disease diagnoses were identified by diagnostic or procedural coding and confirmed by chart review. Our primary endpoint was the pathology for each patient's tumor. Tumors were classified into aggressive or nonaggressive categories based on their histology and grade. We identified 1,150 radical and partial nephrectomies, of which 1,057 met inclusion criteria. Of these, 68 patients (6.4%) had renal dysfunction or a kidney transplant on immunosuppression at time of nephrectomy. After pathologic review, 270 (25%) tumors were classified as aggressive, and 673 (64%) tumors were pT1a or pT1b. On multivariable logistic regression controlling for age and gender, renal dysfunction was not associated with having an aggressive tumor (OR 1.24, 95%CI 0.72–2.15; P = 0.44). We did not observe a relationship between renal dysfunction status and aggressive pathology. These data suggest that renal dysfunction and transplant patients are at similar risk for aggressive pathology as the general population and should be managed according to the same clinical guidelines. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a serious and disabling injury that is often accompanied by neuropathic pain (NeP), which severely affects patients' motor and sensory functions and reduces their quality of life. Currently, there is no specific treatment for treating SCI and relieving the accompanying pain, and we can only rely on medication and physical rehabilitation, both of which are ineffective. Researchers have recently identified a novel class of glial cells, olfactory ensheathing cells (OECs), which originate from the olfactory system. Transplantation of OECs into damaged spinal cords has demonstrated their capacity to repair damaged nerves, improve the microenvironment at the point of injury, and They can also restore neural connectivity and alleviate the patient's NeP to a certain extent. Although the effectiveness of OECs transplantation has been confirmed in experiments, the specific mechanisms by which it repairs the spinal cord and relieves pain have not been articulated. Through a review of the literature, it has been established that the ability of OECs to repair and relieve pain is inextricably linked to its anti-inflammatory and immunomodulatory effects. In this regard, it is imperative to gain a deeper understanding of how OECs exert their anti-inflammatory and immunomodulatory effects. The objective of this paper is to provide a comprehensive overview of the mechanisms by which OECs exert anti-inflammatory and immunomodulatory effects. We aim to manipulate the immune microenvironment at the transplantation site through the intervention of cytokines and immune cells, with the goal of enhancing OECs' function or creating a conducive microenvironment for OECs' survival. This approach is expected to improve the therapeutic efficacy of OECs in clinical settings. However, numerous fundamental and clinical challenges remain to be addressed if OEC transplantation therapy is to become a standardized treatment in clinical practice. [ABSTRACT FROM AUTHOR]

• The adverse immune microenvironment ensuing from cartilage injury, coupled with the intrinsic property of the tissue characterized by limited cellularity, has posed a significant challenge to the reconstruction of cartilage defect. • Enzymatic treatment converts small intestinal submucosa (SIS) into a hydrogel form, not only providing a scaffold for cells engaged and achieving prolonged drug release, but also exhibiting excellent immunomodulatory effects. • Kartogenin (KGN) recruits the endogenous BMSCs of the host and directly enhances their chondrogenic differentiation, thereby achieving cartilage repair and regeneration without cell transplantation. • Leveraging the combined effects of the SIS hydrogel and KGN, this innovative composite material provides a simple yet effective method for expediting the repair and regeneration of cartilage defects. Articular cartilage is crucial for the functional integrity of joints yet vulnerable to a spectrum of injuries. The adverse immune microenvironment ensuing from injury, coupled with the intrinsic property of the tissue characterized by limited cellularity, poses a significant challenge to the reconstruction of cartilage defect. In this study, an extracellular matrix hydrogel derived from porcine small intestinal submucosa (SIS) with encapsulation of Kartogenin (KGN) has been designed for the cartilage repair and regeneration. The SIS hydrogel, which possessed a three-dimensional porous structure akin to the natural cartilage, has provided a scaffold essential for the progenitor cells engaged in the repair process and sustained release of KGN. As shown by in vitro experiments, the KGN could recruit host endogenous bone marrow-derived mesenchymal stem cells (BMSCs) and induce them to differentiate into chondrocytes, thus enabling in situ cartilage regeneration without cell transplantation. Notably, the bioactive component of SIS was further revealed to possess excellent immunomodulatory capacity to induce the phenotypic shift from M1 to M2 macrophages, which could enhance the chondrogenic differentiation of BMSCs indirectly. Additionally, in vivo experiments showed that the regenerated tissues of the composite SIS hydrogel group were close to the natural hyaline cartilage. Leveraging the combined effects of KGN and SIS hydrogel, this innovative composite material shows great potential as a biomaterial for effective cartilage repair and regeneration. [ABSTRACT FROM AUTHOR]

The aim of regenerative medicine is to restore specific functions to damaged cells or tissues. A crucial aspect of success lies in effectively reintegrating these cells or tissues within the recipient organism. This is particularly pertinent for diabetes, where islet function relies on the close connection of beta cells to the bloodstream for glucose sensing and insulin release. Central to this approach is the need to establish a fast connection with the host's vascular system. In this review, we explore the intricate relationships between endocrine, vascular, and immune cell interactions in transplantation outcomes. We also delve into recent strategies aimed at enhancing engraftment, along with the utilization of in vitro platforms to model cellular interactions. [ABSTRACT FROM AUTHOR]

Natural killer T cells (NKT cells) are a unique subset of the immune system that possess characteristics of both an innate and adaptive immune response. This study reviews the reported roles of NKT cells in different solid transplantations such as cardiac, skin, liver, and corneal grafts as well as investigates a novel role of NKT cells in steroid-resistant corneal rejections. It is unknown why there is late corneal graft rejection despite being treated with immunosuppression. Our experimental data suggests NKT cells are playing a crucial part in steroid-resistant late graft rejections. While the pathophysiology of acute rejection is better understood, the process of chronic graft rejection is much less clear. Our data suggests NKT cells as a potential therapeutic target to prevent chronic transplant rejection which needs further investigation. [ABSTRACT FROM AUTHOR]

Genetically modified dendritic cells (DCs) modulate the alloimmunity of T lymphocytes by regulating antigen presentation. We generated mice with specific deletion of the X-box-binding protein 1 (XBP1) allele in bone marrow cells and cultured bone marrow-derived DCs (Xbp1 −/− BMDCs) from these animals. We then tested the phenotype of Xbp1 −/− BMDCs, evaluated their capability to activate allogeneic T cells and investigated their mechanistic actions. We developed a mouse model of allogeneic heart transplantation in which recipients received PBS, Xbp1 −/− BMDCs, a suboptimal dose of cyclosporine A (CsA), or Xbp1 −/− BMDCs combined with a suboptimal dose of CsA to evaluate the effects of Xbp1 −/− BMDC transfusion on alloimmunity and on the survival of heart allografts. The deletion of XBP1 in BMDCs exploited the IRE1-dependent decay of TAPBP mRNA to reduce the expression of MHC-I on the cell surface, altered the capability of BMDCs to activate CD8+ T cells, and ultimately suppressed CD8+ T-cell-mediated allogeneic rejection. The adoptive transfer of Xbp1 −/− BMDCs inhibited CD8+ T-cell-mediated rejection. In addition, XBP1-deficient BMDCs were weak stimulators of allogeneic CD4+ T cells despite expressing high levels of MHC-II and costimulatory molecules on their cell surface. Moreover, the adoptive transfer of Xbp1 −/− BMDCs inhibited the production of circulating donor-specific IgG. The combination of Xbp1 −/− BMDCs and CsA treatment significantly prolonged the survival of allografts compared to CsA alone. The deletion of XBP1 induces immunosuppressive BMDCs, and treatment with these immunosuppressive BMDCs prevents alloimmune rejection and improves the outcomes of heart transplantation. This finding provides a promising therapeutic target in combating transplant rejection and expands knowledge of inducing therapeutic DCs. [Display omitted] [ABSTRACT FROM AUTHOR]

A Stereotaxic Atlas of the Human Lumbar-Sacral Spinal Cord has been created to provide an anatomical basis for radiologic and ultrasonic imaging and electrophysiological examination, which are used to target the placement of lumbar-sacral epidural stimulating electrodes and cellular transplantation in order to restore movement in individuals with sustained spinal cord injury or a degenerative disorder of the spinal cord. Through the availability of an atlas that exhibits axial images of the cytoarchitecture of each cord segment with a stereotaxic millimeter grid of dorsal-ventral depth from the midline dorsal surface of the cord and right–left distances from the midline of the cord, neuromodulation, and cellular therapy would undoubtedly be made not only more precise but also safer for patients. The atlas is based upon dimension measurements and subsequent serial sectioning, staining and high-resolution digital imaging of the lumbar–sacral enlargement of 20 adult human spinal cords. Nissl stained cross-sections from cord segments L1-S3 illustrate the cytoarchitecture and stereotactic coordinates. The atlas provides an anatomical basis for radiologic and physiologic confirmation of target localization in the lumbar-sacral spinal cord. [ABSTRACT FROM AUTHOR]

In a recent study, Shvedov and colleagues used live two-photon imaging in transgenic zebra finches to reveal migration patterns of neuroblasts through the complex environment of the postembryonic brain. This study highlights the value of ubiquitin C/green fluorescent protein (UBC-GFP) transgenic zebra finches in studying adult neurogenesis and advances our understanding of dispersed long-distance neuronal migration in the adult brain, shedding light on this understudied phenomenon. [ABSTRACT FROM AUTHOR]

T cell immunoglobulin domain, and mucin domain-3 (Tim-3) is associated with immunosuppression, immune tolerance, and rejection after organ transplantation, but there are no reports of rejection after human liver transplantation. This study aimed to detect Tim-3 expression after liver transplantation to determine whether Tim-3 can be used as a noninvasive index to predict immune rejection. Quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay were performed on healthy people and patients with liver transplantation to detect Tim-3 and cytokines. Hepatic biochemical test was used to detect liver function. The study conforms to the provisions of the Declaration of Helsinki and Istanbul. The expression of Tim-3, alanine aminotransferase, and aspartate aminotransferase increased first and then decreased, whereas the cytokines showed upward trend. There was no significant difference in the expression of Tim-3 between preoperative patients and normal people (P >.05), whereas the expression of Tim-3 was significantly higher on the third day after operation than that before operation (P <.05). The expression of Tim-3, alanine aminotransferase, and aspartate aminotransferase peaked only once in most liver transplantation patients, but there were 3 patients that were exceptions. Tim-3 could be used as a potential biomarker to predict rejection after liver transplantation. [ABSTRACT FROM AUTHOR]

Background Regulatory T cells (Tregs) are important for maintaining immune homeostasis, limiting kidney transplant rejection, and promoting transplant tolerance. Tregs are characterized as CD4 + CD25+ T cells and the transcription factor Foxp3; they constitute 5–10% of all peripheral CD4+ T cells in healthy humans. The reduction in Treg cells after transplantation may be a predictive factor in graft rejection. Therefore, in this study, we investigated the association between Tregs and short-term graft outcomes in renal transplant recipients. Methods This prospective observational study included 50 patients of both sexes, aged between 18 and 60 years, with end-stage renal disease (ESRD), and who underwent kidney transplantation at the Nizams Institute of Medical Sciences. Flow cytometry was used to measure the percentage of Tregs (CD4 + CD25+) pre-transplant (baseline) and monthly post-transplant in 50 transplant recipients and 20 healthy controls (HC) over six months. The correlation between Treg percentages and graft outcomes was analyzed. Results The percentage of Tregs (Treg%) was significantly lower in ESRD patients before transplantation (baseline) than in the HCs [median 8.5% vs. 14.25%; p < 0.01]. After transplantation, Treg% decreased significantly within a week after grafting compared to the baseline pre-transplant level [median 5.13% vs. 8.5%; p < 0.01]. Moreover, Treg% was lower in the older (> 40 years) than that in the younger age group at one week after transplantation (p > 0.001). Treg% (CD4 + CD25+) was significantly lower in patients with deceased donor renal transplantation (DDRT) than in live renal transplantation (LRT) within the first week of transplantation [median 2.16% vs. 4.6%; p < 0.05] and at the time of graft rejection [median 3.2% vs. 9.2%; p < 0.001]. Induction therapy with anti-IL-2 receptor monoclonal antibody (IL-2RB) lowered Tregs to a greater extent than anti-thymoglobulin (ATG) therapy and no induction therapy [median 3.22% vs. 5.47%, 8.4%, p < 0.05]. In contrast, an increased Treg% was observed in transplant recipients with normal kidney graft function within six months after transplantation compared with the pre-transplant baseline level [median 11.54% vs. 8.5; p < 0.001]. ROC analysis of graft rejection resulted in an area under the curve (AUC) of 0.8 with a p-value <0.05. Conclusion Within the first week after transplantation, the percentage of pre-transplant Tregs was significantly decreased compared to that in age- and sex-matched HC. The percentage of Tregs was also lower in patients with advanced age, DDRT, and those who received IL-2RB induction therapy. Patients who experienced graft rejection had lower Treg% compared to their pre-transplant levels. In contrast, patients with normal graft function at six months showed increased Treg%. Together, these results suggest that Treg% measurements are correlated with clinical outcomes. [ABSTRACT FROM AUTHOR]

To date, the wide application of cell-based biomaterials in tissue engineering and regeneration is remarkably hampered by immune rejection. Reducing the immunogenicity of cell-based biomaterials has become the latest direction in biomaterial research. Recently, genetically modified cell-based biomaterials with immunomodulatory genes have become a feasible solution to the immunogenicity problem. In this review, recent advances and future challenges of genetically modified immunomodulatory cell-based biomaterials are elaborated, including fabrication approaches, mechanisms of common immunomodulatory genes, application and, more importantly, current preclinical and clinical advances. The fabrication approaches can be categorized into commonly used (e.g., virus transfection) and newly developed approaches. The immunomodulatory mechanisms of representative genes involve complicated cell signaling pathways and metabolic activities. Wide application in curing multiple end-term diseases and replacing lifelong immunosuppressive therapy in multiple cell and organ transplantation models is demonstrated. Most significantly, practices of genetically modified organ transplantation have been conducted on brain-dead human decedent and even on living patients after a series of experiments on nonhuman primates. Nevertheless, uncertain biosecurity, nonspecific effects and overlooked personalization of current genetically modified immunomodulatory cell-based biomaterials are shortcomings that remain to be overcome. [Display omitted] • Cell-based biomaterials can be genetically modified with immunomodulatory genes. • Immunomodulatory genes help alleviate immune rejection of cell-based biomaterials. • Fabrication processes include common and newly developed methods. • Clinical/preclinical practices of gene-edited biomaterial transplantation. • Challenges: antigen elimination, systemic administration, individualization. [ABSTRACT FROM AUTHOR]

Angiogenesis is considered a crucial event for dental pulp regeneration. The purpose of this study was to demonstrate neovascularization during coronal pulp regeneration in rat molars using rat dental pulp cells (rDPCs) and to examine whether rDPC-endothelial cell interactions promote proangiogenic capacity in vitro. Maxillary first molars of Wistar rats (n = 42) were pulpotomized and rDPCs isolated from incisors were implanted with a porous poly (l -lactic acid) (PLLA) scaffold and hydrogel (Matrigel). After 3, 7, and 14 days, coronal pulp tissues were examined histologically and by nestin and CD146 immunohistochemistry. rDPCs and rat dermal microvascular endothelial cells (rDMECs) were cocultured for 4 days and vascular endothelial growth factor (VEGF) synthesis and angiogenic factor gene expression were determined by enzyme-linked immunosorbent assays and real-time polymerase chain reaction, respectively. Effects of cocultured medium on tube formation by rDMECs were also evaluated. Implantation of rDPC/PLLA/Matrigel induced coronal pulp regeneration with dentin bridge formation and arrangement of nestin-positive odontoblast-like cells at 14 days. PLLA/Matrigel without rDPCs did not induce pulp regeneration. CD146-positive blood vessels increased in density in the remaining pulp tissues at 3 and 7 days, and in the regenerated pulp tissue at 14 days. rDPC/DMEC coculture significantly promoted VEGF secretion and mRNA expression of nuclear factor-kappa B, angiogenic chemokine CXCL1 , and chemokine receptor CXCR1. Cocultured medium significantly promoted tube formation. Coronal pulp regeneration with rDPC/PLLA/Matrigel was accompanied by neovascularization. rDPC-rDMEC interactions may promote angiogenic activity represented by proangiogenic factor upregulation and tube formation in vitro. [ABSTRACT FROM AUTHOR]

This work establishes the design of a fully synthetic, shear-thinning hydrogel platform that is injectable and can isolate engineered, allogeneic cell therapies from the host. We utilized RAFT to generate a library of linear random copolymers of N,N-dimethylacrylamide (DMA) and 2-vinyl-4,4-dimethyl azlactone (VDMA) with variable mol% VDMA and degree of polymerization. Poly(DMA- co -VDMA) copolymers were subsequently modified with either adamantane (Ad) or β-cyclodextrin (Cd) through amine-reactive VDMA to prepare hydrogel precursor macromers containing complementary guest-host pairing pendant groups that, when mixed, form shear-thinning hydrogels. Rheometric evaluation of the hydrogel library enabled identification of lead macromer structures comprising 15 mol% pendants (Ad or Cd) and a degree of polymerization of 1000; mixing of these Ad and Cd functionalized precursors yielded hydrogels possessing storage modulus above 1000 Pa, tan(δ) values below 1 and high yield strain, which are target characteristics of robust but injectable shear-thinning gels. This modular system proved amenable to nanoparticle integration with surface-modified nanoparticles displaying Ad. The addition of the Ad-functionalized nanoparticles simultaneously improved mechanical properties of the hydrogels and enabled extended hydrogel retention of a model small molecule in vivo. In studies benchmarking against alginate, a material traditionally used for cell encapsulation, the lead hydrogel showed significantly less fibrous encapsulation in a subcutaneous implant site. Finally, this platform was utilized to encapsulate and extend in vivo longevity of inducible transgene-engineered mesenchymal stem cells in an allogeneic transplant model. The hydrogels remained intact and blocked infiltration by host cells, consequently extending the longevity of grafted cell function relative to a benchmark, shear-thinning hyaluronic acid-based gel. In sum, the new synthetic, shear-thinning hydrogel system presented here shows potential for further development as an injectable platform for delivery and in situ drug modulation of allograft and engineered cell therapies. [Display omitted] [ABSTRACT FROM AUTHOR]

Breeding programs for the tiger puffer (Takifugu rubripes), a prominent species in East Asian aquaculture, are underway to establish aquaculture strains with economically desirable genetic traits. However, their brood stocks have large body sizes and require a long time to reach sexual maturity. Surrogate broodstock technology involves generating donor-derived gametes from surrogate (recipient) fish via germ cell transplantation. This method offers a promising solution to overcome the challenges faced in tiger puffer breeding. This study established a sterilization technique using a CRISPR-Cas9 mediated knockout line in the grass puffer (T. alboplumbeus), which serves as a suitable surrogate due to its smaller body size and shorter generation time compared to the tiger puffer. We evaluated the potential of germ cell–deficient grass puffers as recipients for the efficient production of donor-derived tiger puffer gametes. The mutated alleles were induced in the crispant resulting from the microinjection of genome editing solution containing single guide RNA targeted to dead end 1 (dnd1) into fertilized eggs and inherited by the F1 generation. Homozygous mutants generated in the F2 generation by crossing F1 heterozygous mutants displayed germ cell deficiency. Histological observations and gene expression analysis revealed sexual dimorphism in the germ cell–deficient gonads of dnd1 homozygous mutants. The incorporation of donor cells into the recipient gonads was confirmed via the intraperitoneal transplantation of tiger puffer testicular cells into dnd1 homozygous mutants. Donor-derived tiger puffer gametogenesis was observed histologically, with only donor-derived tiger puffer sperm successfully produced in recipients with dnd1 homozygous mutations at one year of age. Thus, the use of a germ cell–deficient grass puffer prepared by crossing the dnd1 heterozygous mutant line as a recipient to only produce donor-derived gametes improves the efficiency of surrogate production and may enhance the efficiency of the breeding process in tiger puffer aquaculture. • CRISPR Sterilization: Introduced CRISPR-Cas9 to sterilize grass puffers, facilitating tiger puffer surrogate production. • Streamlined Technique: Utilized dnd1 mutants as effective recipients, accelerating xenogeneic gamete production. • Fast-tracking Aquaculture: Leveraged the smaller, faster-generation grass puffer for quicker tiger puffer strain development. • Genetic Resource Management: dnd1 mutants offer a tool for managing genetic resources, ensuring efficiency and preservation. [ABSTRACT FROM AUTHOR]