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Objectives: This review aimed to gather and summarize the existing information on the clinical application of allogeneic umbilical and placental derivatives in the treatment of temporomandibular joint disorders. Methods: Research on the impact of the use of umbilical and placental derivatives on reducing pain and improving mobility in the temporomandibular joint was included in the article. Medical databases, including ACM, BASE, Cochrane, Scopus, Google Scholar, ClinicalTrials.gov, and PubMed, were searched. The final search was conducted on 20 October 2024. Results: Out of the 43 records found, 5 were considered eligible for further analysis and showed that the use of placental and umbilical derivatives has the greatest potential in the treatment of ankylosis. The intra-articular administration of these tissues into the TMJ brings beneficial results, but they are similar to other, parallel methods, such as PRP or corticosteroids. Conclusions: The studies discussed may guide researchers in expanding clinical trials, particularly by including more patients with TMDs, and have promising potential in ankylotic disorders, where amniotic membrane use has shown clear benefits. [ABSTRACT FROM AUTHOR]

Previous studies have shown that Hypnea musciformis seaweed extracts (HMEs) possess antioxidant properties, but the molecular mechanisms accounting for this activity are not known. Thus, the present study investigated the molecular mechanisms through which HME exerted its antioxidant activity in human mesenchymal stem cells (WJ‐MSCs). After the isolation of HME, its chemical composition was analyzed with gas chromatography mass spectrometry, indicating that it contained amino acids, organic acids, organic amides, sugar alcohols, saturated fatty acids, hydrogenated diterpene alcohols, and other organic compounds. Afterward, HME was shown in vitro to scavenge DPPH·, ABTS·+, ·OH, and O2·− radicals, possess reducing activity, and protect from ROO·‐induced DNA strand breakage. Finally, the results showed that HME treatment of WJ‐MSCs prevented H2O2‐induced oxidative stress by decreasing lipid peroxidation, protein oxidation, reactive oxygen species levels, and DNA damage and by increasing glutathione levels. Moreover, our findings showed for the first time that HME's antioxidant activity in WJ‐MSCs was mediated through the activation of NRF2, which upregulated the expression of the antioxidant proteins GCLC, GSR, HMOX1, SOD1, TXN, and GPX1. These results provide new insights into H. musciformis' antioxidant properties, which could help substantially its use as a food supplement or for developing biofunctional foods. [ABSTRACT FROM AUTHOR]

Abstract Autoimmunity underlies many painful disorders, such as enthesopathies, which localize to the enthesis. From infiltration of the synovium and axial skeleton by B cells, to disturbances in the ratio of M1/M2 enthesis macrophages, to CD8 + T cell mediated inflammation, autoimmune dysregulation is becoming increasingly well characterized in enthesopathies. Tissue resident B cells, macrophages, neutrophils, and T cells have also been localized in healthy human entheses. However, the potential developmental origins, presence, and role of immune cells (ICs) in enthesis development is not known. Here, we use single-cell RNA-sequencing analysis to describe IC subtypes present in the enthesis before, during, and after mineralization, and to infer regulatory interactions between ICs and mesenchymal cells (MCs). We report the presence of nine phenotypically distinct IC subtypes, including B cells, macrophages, neutrophils, and T cells. We find that specific IC subtypes may promote MC-proliferation and differentiation, and that MCs may regulate IC phenotype and autoimmunity. Our findings suggest that bidirectional regulatory interactions between ICs and MCs may be important to enthesis mineralization, and suggest that progenitor MCs have a unique ability to limit autoimmunity during development.

Summary Children diagnosed with acute myeloid leukaemia (paediatric AML [pAML]) have limited treatment options and relapse rates due to chemoresistance and refractory disease are over 30%. Current treatment is cytotoxic and in itself has long‐lasting harsh side effects. New, less toxic treatments are needed. The bone marrow microenvironment provides chemoprotection to leukaemic cells through cell communication and interaction with mesenchymal stem cells (MSCs), but this is not well defined in pAML. Using primary patient material, we identify a cell contact‐independent mechanism of MSC‐mediated chemoprotection involving extrinsic soluble factors that is abrogated through inhibition of the JAK/STAT and ERK pathways. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer is one of the most common cancers in men, and its progression is strongly influenced by the surrounding environment, known as the tumor microenvironment. This is comprised of a variety of cells, including cancer-associated fibroblasts (CAFs), that modulate tumor initiation and progression and may affect treatment strategies. This review focuses on the interactions between fibroblasts and epithelial cancer cells and how these interactions contribute to cancer progression. This knowledge may unveil novel therapeutic approaches that could mitigate aggressiveness and/or render prostate cancer more responsive to current treatments, thus improving patient outcomes. Prostate cancer progression is significantly affected by its tumor microenvironment, in which mesenchymal cells play a crucial role. Stromal cells are modified by cancer mutations, response to androgens, and lineage plasticity, and in turn, engage with epithelial tumor cells via a complex array of signaling pathways and ligand–receptor interactions, ultimately affecting tumor growth, immune interaction, and response to therapy. The metabolic rewiring and interplay in the microenvironment play an additional role in affecting the growth and progression of prostate cancer. Finally, therapeutic strategies and novel clinical trials with agents that target the stromal microenvironment or disrupt the interaction between cellular compartments are described. This review underscores cancer-associated fibroblasts as essential contributors to prostate cancer biology, emphasizing their potential as prognostic indicators and therapeutic targets. [ABSTRACT FROM AUTHOR]

Autoimmunity underlies many painful disorders, such as enthesopathies, which localize to the enthesis. From infiltration of the synovium and axial skeleton by B cells, to disturbances in the ratio of M1/M2 enthesis macrophages, to CD8 + T cell mediated inflammation, autoimmune dysregulation is becoming increasingly well characterized in enthesopathies. Tissue resident B cells, macrophages, neutrophils, and T cells have also been localized in healthy human entheses. However, the potential developmental origins, presence, and role of immune cells (ICs) in enthesis development is not known. Here, we use single-cell RNA-sequencing analysis to describe IC subtypes present in the enthesis before, during, and after mineralization, and to infer regulatory interactions between ICs and mesenchymal cells (MCs). We report the presence of nine phenotypically distinct IC subtypes, including B cells, macrophages, neutrophils, and T cells. We find that specific IC subtypes may promote MC-proliferation and differentiation, and that MCs may regulate IC phenotype and autoimmunity. Our findings suggest that bidirectional regulatory interactions between ICs and MCs may be important to enthesis mineralization, and suggest that progenitor MCs have a unique ability to limit autoimmunity during development. [ABSTRACT FROM AUTHOR]

Background: The mammalian testicular interstitial cells are not well-defined. The present study characterized the interstitial cell types and their turnover dynamics in adult rats. Additionally, the heterogeneity of the mesenchymal population and the effects of Leydig cell elimination on interstitial homeostasis were further analyzed by scRNA-seq datasets and immunocytochemical techniques. Methods: Interstitial cells were defined at the transcriptomic level by scRNA-seq and then confirmed and quantified with protein markers. The dividing activity of the major cell types was determined by continuous EdU labeling of the animals for one week. Some of the rats were also treated with a dose of ethylenedimethylsulfonate (EDS) to examine how the loss of Leydig cells (LCs) could affect interstitial homeostasis for three weeks. Results: Seven interstitial cell types were identified, including cell types (percentage of the whole interstitial population) as follows: Leydig (44.6%), macrophage and dendritic (19.1%), lymphoid (6.2%), vascular endothelial (7.9%), smooth muscle (10.7%), and mesenchymal (11.5%) cells. The EdU experiment indicated that most cell types were dividing at relatively low levels (<9%) except for the mesenchymal cells (MCs, 17.1%). Further analysis of the transcriptome of MCs revealed 4 subgroups with distinct functions, including 1) glutathione metabolism and xenobiotic detoxification, 2) ROS response and AP-1 signaling, 3) extracellular matrix synthesis and binding, and 4) immune response and regulation. Stem LCs (SLCs) are primarily associated with subgroup 3, expressing ARG1 and GAP43. EDS treatment not only eliminated LCs but also increased subgroup 3 and decreased subgroups 1 and 2 of the mesenchymal population. Moreover, EDS treatment increased the division of immune cells by more than tenfold in one week. Conclusion: Seven interstitial cell types were identified and quantified for rat testis. Many may play more diversified roles than previously realized. The elimination of LCs led to significant changes in MCs and immune cells, indicating the importance of LCs in maintaining testicular interstitial homeostasis. [ABSTRACT FROM AUTHOR]

Abstract Background Regeneration of injured tissue is dependent on stem/progenitor cells, which can undergo proliferation and maturation processes to replace the lost cells and extracellular matrix (ECM). Bone has a higher regenerative capacity than other tissues, with abundant mesenchymal progenitor cells in the bone marrow, periosteum, and surrounding muscle. However, the treatment of bone fractures is not always successful; a marked number of clinical case reports have described nonunion or delayed healing for various reasons. Supplementation of exogenous stem cells by stem cell therapy is anticipated to improve treatment outcomes; however, there are several drawbacks including the need for special devices for the expansion of stem cells outside the body, low rate of cell viability in the body after transplantation, and oncological complications. The use of endogenous stem/progenitor cells, instead of exogenous cells, would be a possible solution, but it is unclear how these cells migrate towards the injury site. Methods The chemoattractant capacity of the elastin microfibril interface located protein 2 (Emilin2), generated by macrophages, was identified by the migration assay and LC–MS/MS. The functions of Emilin2 in bone regeneration were further studied using Emilin2 –/– mice. Results The results show that in response to bone injury, there was an increase in Emilin2, an ECM protein. Produced by macrophages, Emilin2 exhibited chemoattractant properties towards mesenchymal cells. Emilin2 –/– mice underwent delayed bone regeneration, with a decrease in mesenchymal cells after injury. Local administration of recombinant Emilin2 protein enhanced bone regeneration. Conclusion Emilin2 plays a crucial role in bone regeneration by increasing mesenchymal cells. Therefore, Emilin2 can be used for the treatment of bone fracture by recruiting endogenous progenitor cells.

Viral infections, including SARS-CoV-2, are accompanied by signs of systemic inflammation, which can cause long-term sequela for the patient. Time-stable changes in the organism may be caused by epigenetic shifts inherited in a series of cell divisions, in particular, by changes in the DNA methylation profile in cells of various organs and tissues in response to proinflammatory cytokines. IL1B is a key inflammatory factor, and it was shown that CpG methylation level in its promoter can change upon pro-inflammatory stimuli, and that it was associated with significant increase in IL1B expression. In particular, a specific CpG site in the promoter of the IL1B gene located 299 bp upstream from the transcription start site (CpG3) was previously shown to be an important player in these processes. In this study, we examined methylation/demethylation levels of this CpG3 in publicly available genome-wide methylation studies. A total of 15 dataset were analyzed that comprised data from stromal cells in normal and inflammation-associated states, immune cells of healthy young and aging donors, patients during COVID-19 and after recovery. The level of CpG3 demethylation was found to be higher in osteoarthritis samples of cartilage as compared to healthy donors in one dataset. In blood samples of patients with rheumatoid arthritis CpG3 demethylation was also found to be statistically higher than in healthy donors. In COVID-19 studies, blood samples obtained from patients with severe symptoms had higher CpG3 demethylation levels compared to samples obtained from patients with mild symptoms and controls. The level of CpG3 demethylation increased with age in healthy people as judged by whole blood samples. The same dependency was seen for in vitro cultures of mesenchymal cells obtained from healthy donors. Taken together we showed that demethylation level of a single CpG site in IL1B promoter increases in several cell types due to conditions associated with local and systemic inflammation, including SARS-CoV-2 infection, and in aging. These data suggest a possibility that a history of conditions associated with inflammation within an organism may be recorded, preserved, and encoded in its DNA methylation pattern. While the specificity of these "records of inflammation" is an open question, decoding the history of pathological events associated with inflammation that had been faced by the organism is an intriguing possibility. [ABSTRACT FROM AUTHOR]

Organoid models have become an integral part of the research methodology in the lung field. These systems allow for the study of progenitor and stem cell self-renewal, self-organization, and differentiation. Distinct models of lung organoids mimicking various anatomical regions of mature lungs have emerged in parallel to the increased gain of knowledge regarding epithelial stem and progenitor cell populations and the corresponding mesenchymal cells that populate the in vivo niche. In the distal lung, type 2 alveolar epithelial cells (AEC2s) represent a stem cell population that is engaged in regenerative mechanisms in response to various insults. These cells self-renew and give rise to AEC1s that carry out gas exchange. Multiple experimental protocols allowing the generation of alveolar organoids, or alveolospheres, from murine lungs have been described. Among the drawbacks have been the requirement of transgenic mice allowing the isolation of AEC2s with high viability and purity, and the occasional emergence of bronchiolar and bronchioalveolar organoids. Here, we provide a refined gating strategy and an optimized protocol for the generation of alveolospheres from wild-type mice. Our approach not only overcomes the need for transgenic mice to generate such organoids, but also yields a pure culture of alveolospheres that is devoid of bronchiolar and bronchioalveolar organoids. Our protocol contributes to the standardization of this important research tool. [ABSTRACT FROM AUTHOR]

Abstract Background In the choroid plexus and pituitary gland, vasculature is known to have a permeable, fenestrated phenotype which allows for the free passage of molecules in contrast to the blood brain barrier observed in the rest of the CNS. The endothelium of these compartments, along with secretory, neural-lineage cells (choroid epithelium and pituitary endocrine cells) have been studied in detail, but less attention has been given to the perivascular mesenchymal cells of these compartments. Methods The Hic1 CreERT2 Rosa26 LSL−TdTomato mouse model was used in conjunction with a Pdgfra H2B−EGFP mouse model to examine mesenchymal cells, which can be subdivided into Pdgfra+ fibroblasts and Pdgfra− pericytes within the choroid plexus (CP) and pituitary gland (PG), by histological, immunofluorescence staining and single-cell RNA-sequencing analyses. Results We found that both CP and PG possess substantial populations of distinct Hic1+ mesenchymal cells, including an abundance of Pdgfra+ fibroblasts. Within the pituitary, we identified distinct subpopulations of Hic1+ fibroblasts in the glandular anterior pituitary and the neurosecretory posterior pituitary. We also identified multiple distinct markers of CP, PG, and the meningeal mesenchymal compartment, including alkaline phosphatase, indole-n-methyltransferase and CD34. Conclusions Novel, distinct subpopulations of mesenchymal cells can be found in permeable vascular interfaces, including the CP, PG, and meninges, and make distinct contributions to both organs through the production of structural proteins, enzymes, transporters, and trophic molecules.

Background: In the choroid plexus and pituitary gland, vasculature is known to have a permeable, fenestrated phenotype which allows for the free passage of molecules in contrast to the blood brain barrier observed in the rest of the CNS. The endothelium of these compartments, along with secretory, neural-lineage cells (choroid epithelium and pituitary endocrine cells) have been studied in detail, but less attention has been given to the perivascular mesenchymal cells of these compartments. Methods: The Hic1CreERT2 Rosa26LSL−TdTomato mouse model was used in conjunction with a PdgfraH2B−EGFP mouse model to examine mesenchymal cells, which can be subdivided into Pdgfra+ fibroblasts and Pdgfra− pericytes within the choroid plexus (CP) and pituitary gland (PG), by histological, immunofluorescence staining and single-cell RNA-sequencing analyses. Results: We found that both CP and PG possess substantial populations of distinct Hic1+ mesenchymal cells, including an abundance of Pdgfra+ fibroblasts. Within the pituitary, we identified distinct subpopulations of Hic1+ fibroblasts in the glandular anterior pituitary and the neurosecretory posterior pituitary. We also identified multiple distinct markers of CP, PG, and the meningeal mesenchymal compartment, including alkaline phosphatase, indole-n-methyltransferase and CD34. Conclusions: Novel, distinct subpopulations of mesenchymal cells can be found in permeable vascular interfaces, including the CP, PG, and meninges, and make distinct contributions to both organs through the production of structural proteins, enzymes, transporters, and trophic molecules. [ABSTRACT FROM AUTHOR]

Abstract Oral lichen planus is a chronic inflammatory condition that adversely affects the oral mucosa; however, its etiology remains elusive. Consequently, therapeutic interventions for oral lichen planus are limited to symptomatic management. This study provides evidence of the accumulation of senescent mesenchymal cells, CD8 + T cells, and natural killer cells in patients with oral lichen planus. We profiled the patients’ tissues using the National Center for Biotechnology Information Gene Expression Omnibus database and found that senescence-related genes were upregulated in these tissues by gene set enrichment analysis. Immunohistochemical analysis showed increased senescent mesenchymal cells in the subepithelial layer of patients with oral lichen planus. Single-cell RNA-seq data retrieved from the Gene Expression Omnibus database of patients with oral lichen planus revealed that mesenchymal cells were marked by the upregulation of senescence-related genes. Cell-cell communication analysis using CellChat showed that senescent mesenchymal cells significantly influenced CD8 + T cells and natural killer cells via CXCL12-CXCR4 signaling, which is known to activate and recruit CD8 + T cells and NK cells. Finally, in vitro assays demonstrated that the secretion of senescence-associated factors from mesenchymal cells stimulated the activation of T cells and natural killer cells and promoted epithelial cell senescence and cytotoxicity. These findings suggest that the accumulation of mesenchymal cells with senescence-associated secretory phenotype may be a key driver of oral lichen planus pathogenesis.

FOXC2 is a forkhead family transcription factor that plays a critical role in specifying mesenchymal cell fate during embryogenesis. FOXC2 expression is associated with increased metastasis and poor survival in various solid malignancies. Using in vitro and in vivo assays in mouse ovarian cancer cell lines, we confirmed the previously reported mechanisms by which FOXC2 could promote cancer growth, metastasis, and drug resistance, including epithelial-mesenchymal transition, stem cell-like differentiation, and resistance to anoikis. In addition, we showed that FOXC2 expression is associated with vasculogenic mimicry in mouse and human ovarian cancers. FOXC2 overexpression increased the ability of human ovarian cancer cells to form vascular-like structures in vitro, while inhibition of FOXC2 had the opposite effect. Thus, we present a novel mechanism by which FOXC2 might contribute to cancer aggressiveness and poor patient survival.

Renin-Angiotensin-System (RAS) inhibitors remained the only effective nephro-protective treatments until recent landmark trials showed that sodium-glucose co-transporter 2 (SGLT2) inhibitors and non-steroid mineral receptor antagonists added-on RAS inhibitor therapy dramatically slowed renal disease progression in patients with chronic kidney disease (CKD). However, despite this impressive advancement, a substantial proportion of patients remains at high risk of renal and cardiovascular events. Thus, we are still far from achieving the therapeutic ceiling in CKD. However, we are entering a new era in the management of patients with CKD with innovative methodological approaches to test disease-modifying medications in the context of personalized medicine. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is marked by unremitting matrix deposition and architectural distortion. Multiple profibrotic pathways contribute to the persistent activation of mesenchymal cells (MCs) in fibrosis, highlighting the need to identify and target common signaling pathways. The transcription factor nuclear factor of activated T cells 1 (NFAT1) lies downstream of second messenger calcium signaling and has been recently shown to regulate key profibrotic mediator autotaxin (ATX) in lung MCs. Herein, we investigate the role of NFAT1 in regulating fibroproliferative responses during the development of lung fibrosis. Nfat1−/−-deficient mice subjected to bleomycin injury demonstrated improved survival and protection from lung fibrosis and collagen deposition as compared with bleomycin-injured wild-type (WT) mice. Chimera mice, generated by reconstituting bone marrow cells from WT or Nfat1−/− mice into irradiated WT mice (WT→WT and Nfat1−/−→WT), demonstrated no difference in bleomycin-induced fibrosis, suggesting immune influx-independent fibro protection in Nfat1−/− mice. Examination of lung tissue and flow sorted lineageneg/platelet-derived growth factor receptor alpha (PDGFRα)pos MCs demonstrated decreased MC numbers, proliferation [↓ cyclin D1 and 5-ethynyl-2′-deoxyuridine (EdU) incorporation], myofibroblast differentiation [↓ α-smooth muscle actin (α-SMA)], and survival (↓ Birc5) in Nfat1−/− mice. Nfat1 deficiency abrogated ATX expression in response to bleomycin in vivo and MCs derived from Nfat1−/− mice demonstrated decreased ATX expression and migration in vitro. Human IPF MCs demonstrated constitutive NFAT1 activation, and regulation of ATX in these cells by NFAT1 was confirmed using pharmacological and genetic inhibition. Our findings identify NFAT1 as a critical mediator of profibrotic processes, contributing to dysregulated lung remodeling and suggest its targeting in MCs as a potential therapeutic strategy in IPF. NEW & NOTEWORTHY Idiopathic pulmonary fibrosis (IPF) is a fatal disease with hallmarks of fibroblastic foci and exuberant matrix deposition, unknown etiology, and ineffective therapies. Several profibrotic/proinflammatory pathways are implicated in accelerating tissue remodeling toward a honeycombed end-stage disease. NFAT1 is a transcriptional factor activated in IPF tissues. Nfat1-deficient mice subjected to chronic injury are protected against fibrosis independent of immune influxes, with suppression of profibrotic mesenchymal phenotypes including proliferation, differentiation, resistance to apoptosis, and autotaxin-related migration. [ABSTRACT FROM AUTHOR]

Oral lichen planus is a chronic inflammatory condition that adversely affects the oral mucosa; however, its etiology remains elusive. Consequently, therapeutic interventions for oral lichen planus are limited to symptomatic management. This study provides evidence of the accumulation of senescent mesenchymal cells, CD8 + T cells, and natural killer cells in patients with oral lichen planus. We profiled the patients' tissues using the National Center for Biotechnology Information Gene Expression Omnibus database and found that senescence-related genes were upregulated in these tissues by gene set enrichment analysis. Immunohistochemical analysis showed increased senescent mesenchymal cells in the subepithelial layer of patients with oral lichen planus. Single-cell RNA-seq data retrieved from the Gene Expression Omnibus database of patients with oral lichen planus revealed that mesenchymal cells were marked by the upregulation of senescence-related genes. Cell-cell communication analysis using CellChat showed that senescent mesenchymal cells significantly influenced CD8 + T cells and natural killer cells via CXCL12-CXCR4 signaling, which is known to activate and recruit CD8 + T cells and NK cells. Finally, in vitro assays demonstrated that the secretion of senescence-associated factors from mesenchymal cells stimulated the activation of T cells and natural killer cells and promoted epithelial cell senescence and cytotoxicity. These findings suggest that the accumulation of mesenchymal cells with senescence-associated secretory phenotype may be a key driver of oral lichen planus pathogenesis. [ABSTRACT FROM AUTHOR]

Hyaline cartilage, which is characterized by the absence of vascularization and innervation, has minimal self-repair potential in case of damage and defect formation in the chondral layer. Chondrocytes are specialized cells that ensure the synthesis of extracellular matrix components, namely type II collagen and aggregen. On their surface, they express integrins CD44, α1β1, α3β1, α5β1, α10β1, αVβ1, αVβ3, and αVβ5, which are also collagen-binding components of the extracellular matrix. This article aims to contribute to solving the problem of the possible repair of chondral defects through unique methods of tissue engineering, as well as the process of pathological events in articular cartilage. In vitro cell culture models used for hyaline cartilage repair could bring about advanced possibilities. Currently, there are several variants of the combination of natural and synthetic polymers and chondrocytes. In a three-dimensional environment, chondrocytes retain their production capacity. In the case of mesenchymal stromal cells, their favorable ability is to differentiate into a chondrogenic lineage in a three-dimensional culture. [ABSTRACT FROM AUTHOR]

The heart is susceptible to proinflammatory and profibrotic responses after myocardial injury, leading to further worsening of cardiac dysfunction. Important developments in the management of heart failure with reduced ejection fraction have reduced morbidity and mortality; however, these therapies focus on optimizing cardiac function through hemodynamic and neurohormonal pathways and not by repairing the underlying cardiac injury. The potential of cell-based therapy to reverse cardiac injury has received substantial attention. Herein are examined the phase II and III studies of bone marrow-derived mesenchymal STRO-1+ or STRO-1/STRO-3+ precursor cells in patients with ischemic and nonischemic heart failure with reduced ejection fraction, addressing the safety and efficacy of cell-based therapy throughout multiple clinical trials, the optimal dose and the steps toward revolutionizing the treatment of heart failure. Heart disease can occur due to the blockage of blood flow to the heart muscle (heart attack). This damage reduces heart function, in part because of inflammation and fibrosis (scarring). Over time, these problems lead to heart failure and death. Advances in treating heart disease focus on maintaining heart function rather than healing the heart. A cell-based treatment designed to actually repair the heart has been used with some success. In this approach, stem cells are extracted from the bone marrow of a healthy adult, processed and then injected into a patient's diseased heart. This approach is promising, but heart repair remains incomplete. This article looks at a specific type of bone marrow stem cell that has been used as a treatment for patients with heart disease. This cell treatment was recently tested in the largest such study and the first phase III clinical trial to date in the area – the DREAM-HF study. This article addresses the safety and best dosage of these cells and examines how this new approach of cell-based therapy might change how heart disease is treated. This review examines phase II and III studies of bone marrow-derived mesenchymal precursor cells in patients with ischemic and nonischemic heart failure, addressing the safety and efficacy of cell-based therapy, the optimal dose and ways to revolutionize the treatment of heart failure. [ABSTRACT FROM AUTHOR]

Broncho-alveolar lavage (BAL) represents a safe tool for the differential diagnosis of various pulmonary fibrotic diseases. Idiopathic pulmonary fibrosis (IPF) belongs to a heterogeneous group of diseases, interstitial lung disease (ILD), presenting a progressive impairment of pulmonary functions. IPF is characterized by the excessive accumulation of extracellular matrix (ECM) in the alveolar parenchyma that may lead to irreversible pulmonary remodeling. Although the exact pathogenetic mechanisms leading to IPF development are still unclear it has been demonstrated that fibroblasts differentiating toward myofibroblasts are the major actors involved in this process. The possibility of obtaining and expanding fibroblasts from the BAL of ILD patients for research purposes has been recently explored. This approach is discussed here as a reliable chance, helpful to advance the scientific community knowledge and to devise two- and three-dimensional (2D/3D) pre-clinical in vitro models of these diseases, further overcoming technical and ethical concerns related to the use of fibroblasts derived from tissue biopsy.

The study of neurodevelopmental molecular mechanisms in schizophrenia requires the development of adequate biological models such as patient-derived cells and their derivatives. We previously utilized cell lines with neural progenitor properties (CNON) derived from the superior or middle turbinates of patients with schizophrenia and control groups to study schizophrenia-specific gene expression. In this study, we analyzed single-cell RNA seq data from two CNON cell lines (one derived from an individual with schizophrenia (SCZ) and the other from a control group) and two biopsy samples from the middle turbinate (MT) (also from an individual with SCZ and a control). We compared our data with previously published data regarding the olfactory neuroepithelium and demonstrated that CNON originated from a single cell type present both in middle turbinate and the olfactory neuroepithelium and expressed in multiple markers of mesenchymal cells. To define the relatedness of CNON to the developing human brain, we also compared CNON datasets with scRNA-seq data derived from an embryonic brain and found that the expression profile of the CNON closely matched the expression profile one of the cell types in the embryonic brain. Finally, we evaluated the differences between SCZ and control samples to assess the utility and potential benefits of using CNON single-cell RNA seq to study the etiology of schizophrenia. [ABSTRACT FROM AUTHOR]

The capacity for cancer cells to metastasize to distant organs depends on their ability to execute the carefully choreographed processes of cell adhesion and migration. As most human cancers are of epithelial origin (carcinoma), the transcriptional downregulation of adherent/tight junction proteins (e.g., E-cadherin, Claudin and Occludin) with the concomitant gain of adhesive and migratory phenotypes has been extensively studied. Most research and reviews on cell adhesion and migration focus on the actin cytoskeleton and its reorganization. However, metastasizing cancer cells undergo the extensive reorganization of their cytoskeletal system, specifically in originating/nucleation sites of microtubules and their orientation (e.g., from non-centrosomal to centrosomal microtubule organizing centers). The precise mechanisms by which the spatial and temporal reorganization of microtubules are linked functionally with the acquisition of an adhesive and migratory phenotype as epithelial cells reversibly transition into mesenchymal cells during metastasis remains poorly understood. In this Special Issue of "Molecular Mechanisms Underlying Cell Adhesion and Migration", we highlight cell adhesion and migration from the perspectives of microtubule cytoskeletal reorganization, cell polarity and phosphoinositide signaling. [ABSTRACT FROM AUTHOR]

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Simple Summary: In multiple myeloma, malignant plasma cells accumulate in the bone marrow. The symptoms and complications include osteolytic bone disease, anemia, reduced kidney function, immunosuppression, and induction of tumor-associated angiogenesis. Mesenchymal cells are important components of bone marrow niches; studying their dysfunctional activities reveals key features in myeloma pathogenies and improves therapies. We discovered that a subset of mesenchymal cells that express the receptor EDNRA are more prevalent in bone marrow areas infiltrated with tumor cells. In normal conditions, these cells are attached to blood vessels and mediate their functions; but in myeloma they seem to detach and accumulate in the interstitial marrow. The proportion of EDNRA-expressing cells and the expression of EDNRA in bone biopsies is low in premalignant stages and highest in high-risk myeloma patients. EDNRA could serve as a useful novel clinical biomarker of disease progression and dysfunctional bone marrow vasculature. Multiple myeloma (MM) induces dysfunctional bone marrow (BM) mesenchymal cells and neoangiogenesis. Pericytes and smooth muscle cells (SMCs) could detach from vessels and become cancer-associated fibroblasts. We found that the pericyte and SMC marker endothelin receptor type A (EDNRA) is overexpressed in whole MM bone biopsies; we sought to characterize its expression. EDNRA expression gradually increased with disease progression. High-risk MM patients had higher EDNRA expression than low-risk MM patients and EDNRA expression was highest in focal lesions. High EDNRA expression was associated with high expression of pericyte markers (e.g., RGS5, POSTN, and CD146) and the angiogenic marker FLT1. A single-cell analysis of unexpanded BM mesenchymal cells detected EDNRA expression in a subset of cells that coexpressed mesenchymal cell markers and had higher expression of proliferation genes. Immunohistochemistry revealed that the number of EDNRA+ cells in the interstitial BM increased as MM progressed; EDNRA+ cells were prevalent in areas near the MM focal growth. EDNRA+ cells were detached from CD34+ angiogenic cells and coexpressed RGS5 and periostin. Therefore, they likely originated from pericytes or SMCs. These findings identify a novel microenvironmental biomarker in MM and suggest that the presence of detached EDNRA+ cells indicates disrupted vasculature and increased angiogenesis. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate whether fibroblast growth factor 4 (FGF4) and FGF9 are active in dentin differentiation. Dentin matrix protein 1 (Dmp1) -2A-Cre transgenic mice, which express the Cre-recombinase in Dmp1-expressing cells, were crossed with CAG-tdTomato mice as reporter mouse. The cell proliferation and tdTomato expressions were observed. The mesenchymal cell separated from neonatal molar tooth germ were cultured with or without FGF4, FGF9, and with or without their inhibitors ferulic acid and infigratinib (BGJ398) for 21 days. Their phenotypes were evaluated by cell count, flow cytometry, and real-time PCR. Immunohistochemistry for FGFR1, 2, and 3 expression and the expression of DMP1 were performed. FGF4 treatment of mesenchymal cells obtained promoted the expression of all odontoblast markers. FGF9 failed to enhance dentin sialophosphoprotein (Dspp) expression levels. Runt-related transcription factor 2 (Runx2) was upregulated until day 14 but was downregulated on day 21. Compared to Dmp1-negative cells, Dmp1-positive cells expressed higher levels of all odontoblast markers, except for Runx2. Simultaneous treatment with FGF4 and FGF9 had a synergistic effect on odontoblast differentiation, suggesting that they may play a role in odontoblast maturation. [ABSTRACT FROM AUTHOR]

Abstract Since the discovery of group 2 innate lymphoid cells (ILC2s) in 2010, subsequent studies have revealed their developmental pathways, mechanisms of activation and regulation, and immunological roles in tissue homeostasis and tissue-specific diseases in various organs. Although ILC2s are known to express tissue-specific features depending on where they reside, how the surrounding environment affects the functions of ILC2s remains to be fully elucidated. Recent histologic analyses revealed that ILC2s resides in specific perivascular regions in peripheral tissues with their function being controlled by the surrounding cells via cytokines, lipid mediators, neurotransmitters, and cell–cell interactions through surface molecules. This review summarizes the interactions between ILC2s and surrounding cells, including epithelial cells, neurons, immune cells, and mesenchymal cells, with the objective of promoting the development of novel diagnostic and therapeutic methods for ILC2-related diseases.

Introduction: Embryonic stem cells are candidates for the treatment of regenerative medicine, but their use is faced with limitations due to ethical issues. The human umbilical cord-derived mesenchymal stem cells (MSCs) are appropriate options because the cells have no ethical difficulties and have self-renewal. Senescence is known as a gradual functional loss that heterogeneously occurs in multiple organ systems. Objective: The objective of this study was to investigate the cellular senescence process in human umbilical cord Wharton's jelly-derived mesenchymal cells. Materials and Methods: Umbilical cord was obtained from healthy newborns at the General Hospital of Tabriz. Under sterile conditions, Wharton's jelly was removed from the blood vessels and minced into small pieces of about 0.5 mm. These were cultured in Dulbecco's Modified Eagle's Medium (MSC medium). Real-time polymerase chain reaction for p16INK4a and senescence-associated β-galactosidase (SA-β-gal) staining was performed to investigate the cellular senescence process. Results: The results showed the different expressions in the different passages, but it was significantly increased from the fifth passage compared to the first passage. SA-β-gal staining also showed increased colour intensity in the fifth passage compared to the first passage. Conclusion: SA-β-gal is not a specific marker for senescence, while p16INK4a is a specific marker. Further studies are required for the investigation of the senescence mechanism, such as the evaluation of genes involved in the senescence.

Modern day broilers have a great genetic potential to gain heavy bodyweights with a huge metabolic demand prior to their fully mature ages. Moreover, this made the broilers prone to opportunistic pathogens which may enter the locomotory organs under stress causing bacterial chondronecrosis and osteomyelitis (BCO). Such pathogenic colonization is further accelerated by microfractures and clefts that are formed in the bones due to rapid growth rate of the broilers along with ischemia of blood vessels. Furthermore, there are several pathways which alter bone homeostasis like acute phase response, and intrinsic and extrinsic cell death pathways. In contrast, all the affected birds may not exhibit clinical lameness even with the presence of lameness associated factors causing infection. Although Staphylococcus, E. coli, and Enterococcus are considered as common bacterial pathogens involved in BCO, but there exist several other non-culturable bacteria. Any deviation from maintaining a homeostatic environment in the gut might lead to bacterial translocation through blood followed by proliferation of pathogenic bacteria in respective organs including bones. It is important to alleviate dysbiosis of the blood which is analogous to dysbiosis in the gut. This can be achieved by supplementing pro, pre, and synbiotics which helps in providing a eubiotic environment abating the bacterial translocation that was studied to the incidence of BCO. This review focused on potential and novel biomarkers, pathophysiological mechanism, the economic significance of BCO, immune mechanisms, and miscellaneous factors causing BCO. In addition, the role of gut microbiomes along with their diversity and cell culture models from compact bones of chicken in better understanding of BCO were explored. [ABSTRACT FROM AUTHOR]

Type 2 lymphocytes promote both physiologic tissue remodeling and allergic pathology, yet their physical tissue niches are poorly described. Here, we used quantitative imaging to define the tissue niches of group 2 innate lymphoid cells (ILC2s), which are critical instigators of type 2 immunity. We identified a dominant adventitial niche around lung bronchi and larger vessels in multiple tissues, where ILC2s localized with subsets of dendritic and regulatory T cells. However, ILC2s were most intimately associated with adventitial stromal cells (ASCs), a mesenchymal fibroblast-like subset that expresses interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP). In vitro, ASCs produced TSLP that supported ILC2 accumulation and activation. ILC2s and IL-13 drove reciprocal ASC expansion and IL-33 expression. During helminth infection, ASC depletion impaired lung ILC2 and Th2 cell accumulation and function, which are in part dependent on ASC-derived IL-33. These data indicate that adventitial niches are conserved sites where ASCs regulate type 2 lymphocyte expansion and function.

Therapy-related myeloid neoplasms (t-MN) are a late complication of cytotoxic therapy (CT) used in the treatment of both malignant and non-malignant diseases. Historically, t-MN has been considered to be a direct consequence of DNA damage induced in normal hematopoietic stem or progenitor cells (HSPC) by CT. However, we now know that treatment-induced mutations in HSC are not the only players involved in t-MN development but additional factors may contribute to the onset of t-MN. One of the known drivers involved in this field is the bone marrow microenvironment (BMM) and in particular bone marrow mesenchymal stem cells (BM-MSC) whose role in t-MN pathogenesis is the topic of this mini-review. BM-MSC, physiologically, support HSC maintenance, self-renewal, and differentiation, through hematopoietic–stromal interactions and production of cytokines. In addition, BM-MSC maintain the stability of the BM immune microenvironment and reduce the damage caused to HSC by stress stimuli. In t-MN context, chemo/radio-therapy may induce damage to the BM-MSC and likewise alter BM-MSC functions by promoting pro-inflammatory response, clonal selection and/or the production of factors that may favor malignant hematopoiesis. Over the last decade, it has been shown that BM-MSC isolated from patients with de novo and therapy-related MN exhibit decreased proliferative and clonogenic capacity, altered morphology, increased senescence, defective osteogenic differentiation potential, impaired immune-regulatory properties, and reduced ability to support HSC growth and differentiation, as compared to normal BM-MSC. Although the understanding of the genetic and gene expression profile associated with ex vivo-expanded t-MN-MSCs remains limited and debatable, its potential role in prognostic and therapeutic terms is acting as a flywheel of attraction of many researchers.

BackgroundHuman umbilical cord matrix-mesenchymal stromal cells (hUCM-MSC) have demonstrated beneficial effects in experimental acute myocardial infarction (AMI). Reperfusion injury hampers myocardial recovery in a clinical setting and its management is an unmet need. We investigated the efficacy of intracoronary (IC) delivery of xenogeneic hUCM-MSC as reperfusion-adjuvant therapy in a translational model of AMI in swine.MethodsIn a placebo-controlled trial, pot-belied pigs were randomly assigned to a sham-control group (vehicle-injection; n = 8), AMI + vehicle (n = 12) or AMI + IC-injection (n = 11) of 5 × 105 hUCM-MSC/Kg, within 30 min of reperfusion. AMI was created percutaneously by balloon occlusion of the mid-LAD. Left-ventricular function was blindly evaluated at 8-weeks by invasive pressure-volume loop analysis (primary endpoint). Mechanistic readouts included histology, strength-length relationship in skinned cardiomyocytes and gene expression analysis by RNA-sequencing.ResultsAs compared to vehicle, hUCM-MSC enhanced systolic function as shown by higher ejection fraction (65 ± 6% vs. 43 ± 4%; p = 0.0048), cardiac index (4.1 ± 0.4 vs. 3.1 ± 0.2 L/min/m2; p = 0.0378), preload recruitable stroke work (75 ± 13 vs. 36 ± 4 mmHg; p = 0.0256) and end-systolic elastance (2.8 ± 0.7 vs. 2.1 ± 0.4 mmHg*m2/ml; p = 0.0663). Infarct size was non-significantly lower in cell-treated animals (13.7 ± 2.2% vs. 15.9 ± 2.7%; Δ = −2.2%; p = 0.23), as was interstitial fibrosis and cardiomyocyte hypertrophy in the remote myocardium. Sarcomere active tension improved, and genes related to extracellular matrix remodelling (including MMP9, TIMP1 and PAI1), collagen fibril organization and glycosaminoglycan biosynthesis were downregulated in animals treated with hUCM-MSC.ConclusionIntracoronary transfer of xenogeneic hUCM-MSC shortly after reperfusion improved left-ventricular systolic function, which could not be explained by the observed extent of infarct size reduction alone. Combined contributions of favourable modification of myocardial interstitial fibrosis, matrix remodelling and enhanced cardiomyocyte contractility in the remote myocardium may provide mechanistic insight for the biological effect.

Despite the tremendous efforts of many researchers and clinicians, cancer remains the second leading cause of mortality worldwide. Mesenchymal stem/stromal cells (MSCs) are multipotent cells residing in numerous human tissues and presenting unique biological properties, such as low immunogenicity, powerful immunomodulatory and immunosuppressive capabilities, and, in particular, homing abilities. Therapeutic functions of MSCs are mediated mostly by the paracrine effect of released functional molecules and other variable components, and among them the MSC-derived extracellular vesicles (MSC-EVs) seem to be one of the central mediators of the therapeutic functions of MSCs. MSC-EVs are membrane structures secreted by the MSCs, rich in specific proteins, lipids, and nucleic acids. Amongst these, microRNAs have achieved the most attention currently. Unmodified MSC-EVs can promote or inhibit tumor growth, while modified MSC-EVs are involved in the suppression of cancer progression via the delivery of therapeutic molecules, including miRNAs, specific siRNAs, or suicide RNAs, as well as chemotherapeutic drugs. Here, we present an overview of the characteristics of the MSCs-EVs and describe the current methods for their isolation and analysis, the content of their cargo, and modalities for the modification of MSC-EVs in order for them to be used as drug delivery vehicles. Finally, we describe different roles of MSC-EVs in the tumor microenvironment and summarize current advances of MCS-EVs in cancer research and therapy. MSC-EVs are expected to be a novel and promising cell-free therapeutic drug delivery vehicle for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Cellular therapy (CT) can be defined as the transference into a person of healthy cells to correct defective functions. Yesterday (1950–2010), CT consisted mostly of hematopoietic transplants for the treatment of a variety of hematological disorders. Interestingly, during that period of time other cell types with therapeutic potential—including certain lymphoid populations and other nonhematopoietic cells—were discovered and characterized; thus, CT became a promising discipline for the treatment of a broader diversity of diseases. Today (2011–2023), CT has significantly grownup through preclinical studies and clinical trials, and it is currently progressing toward its consolidation as one of the pillars of medicine in the 21st century. Indeed, different types of stem cells (e.g., hematopoietic, mesenchymal, neural, and pluripotent), as well as different lymphoid and myeloid cell populations (e.g., TILs, CAR-Ts, CAR-NKs, and DUOC-01) are being used in clinical settings or are being tested in clinical trials. For the past decade, several CT modalities have been developed, and today, many of them are being used in the clinic. Tomorrow (2024–2040), already established CT modalities will surely be improved and applied more frequently, and novel therapies (that will include cell types such as iPSCs) will enter and expand within the clinical ground. It is noteworthy, however, that despite significant advancements and achievements, problems still need to be solved and obstacles need to be overcome. Technical, ethical, and economic issues persist and they need to be addressed. Undoubtedly, exciting times of challenges and opportunities are coming ahead in the CT arena. [ABSTRACT FROM AUTHOR]

Platelet-rich fibrin (PRF) has a potent anti-inflammatory activity but the components mediating this effect remain unknown. Blood lipids have anti-inflammatory properties. The question arises whether this is also true for the lipid fraction of PRF. To answer this question, lipid fractions of solid and liquid PRF were tested for their potential to lower the inflammatory response of ST2 bone marrow stromal cells and primary bone marrow macrophages exposed to IL1β and TNFα, and LPS, respectively. Cytokine production and the underlying signalling pathway were analysed by RT-PCR, immunoassays, and Western blotting. We report here that lipids from solid and liquid PRF substantially lowered cytokine-induced expression of IL6, CCL2 and CCL5 in ST2 cells. Moreover, the inflammatory response induced by Pam3CSK4, the agonist of Toll-like receptor (TLR) TLR2, was partially reduced by the lipid extracts in ST2 cells. The PRF lipids further reduced the LPS-induced expression of IL1β, IL6 and CCL5 in macrophages at the transcriptional level. This was confirmed by showing the ability of PRF lipids to diminish IL6 at the protein level in ST2 cells and macrophages. Likewise, PRF lipid extracts reduced the phosphorylation of p38 and JNK and moderately decreased the phosphorylation of NFκB-p65 in ST2 cells. These findings suggest that the lipid fraction is at least partially responsible for the anti-inflammatory activity of PRF in vitro. [ABSTRACT FROM AUTHOR]

Microalgae as unicellular eukaryotic organisms demonstrate several advantages for biotechnological and biological applications. Natural derived microalgae products demand has increased in food, cosmetic and nutraceutical applications lately. The natural antioxidants have been used for attenuation of mitochondrial cell damage caused by oxidative stress. This study evaluates the in vitro protective effect of Chlorella vulgaris bioactive extracts against oxidative stress in human mesenchymal stromal/stem cells (MSCs). The classical solid-liquid and the supercritical extraction, using biomass of commercially available and laboratory cultivated C. vulgaris, are employed. Oxidative stress induced by 300 μM H2O2 reduces cell viability of MSCs. The addition of C. vulgaris extracts, with increased protein content compared to carbohydrates, to H2O2 treated MSCs counteracted the oxidative stress, reducing reactive oxygen species levels without affecting MSC proliferation. The supercritical extraction was the most efficient extraction method for carotenoids resulting in enhanced antioxidant activity. Pre-treatment of MSCs with C. vulgaris extracts mitigates the oxidative damage ensued by H2O2. Initial proteomic analysis of secretome from licensed (TNFα-activated) MSCs treated with algal extracts reveals a signature of differentially regulated proteins that fall into clinically relevant pathways such as inflammatory signaling. The enhanced antioxidative and possibly anti-inflammatory capacity could be explored in the context of future cell therapies. [ABSTRACT FROM AUTHOR]

The skeleton is a metabolically active organ that is continuously remodeled throughout our lives. This remodeling entails a balance between the formation of bone conducted by the osteoblasts and resorption by osteoclasts. Osteocytes regulate these two processes and their mechanical stimulation is essential to maintain the good functioning of bones and prevent diseases such as osteoporosis. Osteocyte stimulation causes an alteration in the production and secretion of signaling molecules that regulate osteoblast and osteoclast activity. Mesenchymal stem cells have been proposed as a possible cellular therapy for the regeneration of different tissues including bone tissue. We hypothesize in the present study that the secretome of mechanically stimulated osteocytic mouse cells affect the proliferative, adhesive capacity and gene expression of undifferentiated mesenchymal cells and preosteoblastic mesenchymal cells. To that end, the above-mentioned biological processes were analyzed in continuous preosteoblastic cellular lines and mouse mesenchymal cells in the presence of the medium conditioned by MLO-Y4 osteocytic cells after undergoing a mechanical stimulus by fluid flow. It was observed that proliferation increased in both cellular lines in the presence of secretome of mechanically stimulated osteocytes versus control while non-mechanically stimulated osteocytes caused its reduction. It was also possible to observe an increased adhesive capacity of C3H/10T1/2 cells after stimulation with the secretome of mechanically stimulated osteocytes. Regarding gene expression, only the adipogenic factor PPARγ underwent alterations in MC3T3-E1 cells by the secretome of osteocytes. These studies indicate that osteocytes can modify the biological behavior of mesenchymal cells by the secretion of soluble factors. [ABSTRACT FROM AUTHOR]

Mesenchymal (human amniotic mesenchymal stem cell [HAMSC]) and epithelial cells (human amnion epithelial cell [HAEC]) derived from human amniotic membranes possess characteristics of pluripotency. However, the pluripotency of HAMSC and HAEC are sustained only for a finite period. This in vitro cell growth can be extended by cell immortalisation. Many well‐defined immortalisation systems have been used for artificially overexpressing genes such as human telomerase reverse transcriptase in HAMSC and HAEC leading to controlled and prolonged cell proliferation. In recent years, much progress has been made in our understanding of the cellular machinery that regulates the cell cycle when immortalised. This review summarises the current understanding of molecular mechanisms that contribute to cell immortalisation, the strategies that have been employed to immortalise amnion‐derived cell types, and their likely applications in regenerative medicine. [ABSTRACT FROM AUTHOR]

Summary: Despite the inclusion of inherited myeloid malignancies as a separate entity in the World Health Organization Classification, many established predisposing loci continue to lack functional characterization. While germline mutations in the DNA repair factor ERCC excision repair 6 like 2 (ERCC6L2) give rise to bone marrow failure and acute myeloid leukaemia, their consequences on normal haematopoiesis remain unclear. To functionally characterise the dual impact of germline ERCC6L2 loss on human primary haematopoietic stem/progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs), we challenged ERCC6L2‐silenced and patient‐derived cells ex vivo. Here, we show for the first time that ERCC6L2‐deficiency in HSPCs significantly impedes their clonogenic potential and leads to delayed erythroid differentiation. This observation was confirmed by CIBERSORTx RNA‐sequencing deconvolution performed on ERCC6L2‐silenced erythroid‐committed cells, which demonstrated higher proportions of polychromatic erythroblasts and reduced orthochromatic erythroblasts versus controls. In parallel, we demonstrate that the consequences of ERCC6L2‐deficiency are not limited to HSPCs, as we observe a striking phenotype in patient‐derived and ERCC6L2‐silenced MSCs, which exhibit enhanced osteogenesis and suppressed adipogenesis. Altogether, our study introduces a valuable surrogate model to study the impact of inherited myeloid mutations and highlights the importance of accounting for the influence of germline mutations in HSPCs and their microenvironment. [ABSTRACT FROM AUTHOR]

Understanding the complex processes of fetal wound healing and skin regeneration can help to improve fetal surgery. As part of the integumentary system, the skin protects the newborn organism against environmental factors and serves various functions. Glucocorticoids can enter the fetal circulatory system by either elevated maternal stress perception or through therapeutic administration and are known to affect adult skin composition and wound regeneration. In the present study, we aimed at investigating the effects of local glucocorticoid administration on the process of embryonic wound healing. We performed in-ovo bead implantation of dexamethasone beads into skin incisional wounds of avian embryos and observed the local effects of the glucocorticoid on the process of skin regeneration through histology, immunohistochemistry and in-situ hybridization, using vimentin, fibronectin, E-cadherin, Dermo-1 and phospho-Histone H3 as investigational markers. Local glucocorticoid administration decelerated the healing of the skin incisional wounds by impairing mesenchymal contraction and re-epithelialization resulting in morphological changes, such as increased epithelialization and disorganized matrix formation. The results contribute to a better understanding of scarless embryonic wound healing and how glucocorticoids might interfere with the underlying molecular processes, possibly indicating that glucocorticoid therapies in prenatal clinical practice should be carefully evaluated. [ABSTRACT FROM AUTHOR]