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Mesenchymal stem/stromal cells (MSCs) are adult multipotent cells with self-renewal potential and the ability to differentiate into specialized cells. MSCs home in various tissues and can be isolated using simple methods. Because of this feasibility in the isolation and culture of MSCs in vitro, many scientists have focused on the therapeutic applications of MSCs for various diseases and conditions. The selection of the tissue source to obtain MSCs mainly depends on the availability of the tissue, the patient’s health status, as well as the expertise of the researcher. However, some studies indicate that MSCs derived from different tissue sources are not the same and possess different regenerative capacities. Therefore, in this review, we have collected and summarized the results from studies that have performed head-to-head comparisons between MSCs isolated from different tissues. Despite the assessment method discrepancy between studies, results from these studies reveal that MSCs derived from different tissue sources are not the same. Some such as umbilical cord-derived MSCs and menstrual blood-derived MSCs were identified with robust angiogenic potentials. However, cord blood-derived MSCs possessed a strong cartilage repair capacity. Further investigations are required to establish certain capabilities for MSCs derived from a particular tissue origin. Nevertheless, it is recommended to consider the possibility of functional variations between MSCs isolated from distinct tissue origins when applying MSCs in clinics.

Menstrual blood is a rich source of mesenchymal stem/stromal cells (MenSCs) with a diverse potential to differentiate into various cell types. Similar to other cells, MenSCs produce extracellular vesicles from which, small extracellular vesicles have attracted much interest due to their therapeutic and regenerative capacities. Here using in vitro approaches, several properties of MenSC-derived small extracellular vesicles (MEX) have been investigated. HUVEC angiogenesis assay was used to evaluate the proangiogenic function of MEX. The immune regulatory property of MEX was assessed using a T cell proliferation assay. Proliferation, migration, and gene expression of primary fibroblasts were selected to determine the scar-related activity of MEX. Finally, the anti-cancer effect of MEX on the proliferation of cancerous cell lines was tested. Our results demonstrated that the small extracellular vesicles isolated from MenSCs have proangiogenic and immune-suppressive abilities. Moreover, these vesicles performed as an anti-proliferative agent for cancerous cell lines. MEX was also able to reduce the migration of primary fibroblasts. In summary, MEX has shown promising in vitro characteristics for regenerative applications. They may offer a great cell-free strategy with therapeutic potential for a diverse range of diseases. For future therapeutic applications and further clinical translation, more studies are needed to elucidate the involved mechanisms.

COVID-19 disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), started in December 2019 in Wuhan, China, and quickly became the global pandemic. The high spread rate, relatively high mortality rate, and the lack of specific medicine have led researchers and clinicians worldwide to find new treatment strategies. Unfortunately, evidence shows that the virus-specific receptor Angiotensin-Converting Enzyme 2 (ACE-2) is present on the surface of most cells in the body, leading to immune system dysfunction and multi-organ failure in critically ill patients. In this context, the use of Mesenchymal Stem Cells (MSCs) and their secret has opened new therapeutic horizons for patients due to the lack of ACE2 receptor expression. MSCs exert their beneficial therapeutic actions, particularly anti-inflammatory and immunomodulatory properties, mainly through paracrine effects which are mediated by exosomes. Exosomes are bilayer nanovesicles that carry a unique cargo of proteins, lipids and functional nucleic acids based on their cell origin. This review article aims to investigate the possible role of exosomes and the underlying mechanism involved in treating COVID-19 disease based on recent findings.

Using cell-based engineered skin is an emerging strategy for treating difficult-to-heal wounds. To date, much endeavor has been devoted to the fabrication of appropriate scaffolds with suitable biomechanical properties to support cell viability and growth in the microenvironment of a wound. The aim of this research was to assess the impact of adipose tissue-derived mesenchymal stem cells (AD-MSCs) and keratinocytes on gelatin/chitosan/β-glycerol phosphate (GCGP) nanoscaffold in full-thickness excisional skin wound healing of rats. For this purpose, AD-MSCs and keratinocytes were isolated from rats and GCGP nanoscaffolds were electrospun. Through an in vivo study, the percentage of wound closure was assessed on days 7, 14, and 21 after wound induction. Samples were taken from the wound sites in order to evaluate the density of collagen fibers and vessels at 7 and 14 days. Moreover, sampling was done on days 7 and 14 from wound sites to assess the density of collagen fibers and vessels. The wound closure rate was significantly increased in the keratinocytes-AD-MSCs-scaffold (KMS) group compared with other groups. The expressions of vascular endothelial growth factor, collagen type 1, and CD34 were also significantly higher in the KMS group compared with the other groups. These results suggest that the combination of AD-MSCs and keratinocytes seeded onto GCGP nanoscaffold provides a promising treatment for wound healing.

Type 1 diabetes, has been recognized as an autoimmune disease. Like other immunological conditions, regulation of immune response is a key strategy to control the autoimmunity in diabetic patients. Mesenchymal stem cells have been shown to have a distinct potential in modulating the immune reactions. However, treatment with stem cells is combined with concerns about safety issues. To overcome these concerns, in this study, we have utilized the regenerative potential of exosomes isolated from menstrual blood-derived mesenchymal stem cells to restore the β-cell mass and insulin production in type 1 diabetes. Exosomes are nanovesicles containing various cargos involved in cellular communications. Streptozotocin was used to induce islet destruction and diabetes in male Wistar rats. Then, exosomes were intravenously injected into animals at different time points and in a single or repeated therapeutic doses. After about 6 weeks, animals were euthanized and the pancreas was analyzed for the presence of the regenerated β islets as well as the insulin secretion. The non-fasting blood glucose and the serum insulin level were also monitored during the study. Our results represented that menstrual blood-derived mesenchymal stem cell-derived exosomes enhance the β-cell mass and insulin production in the pancreas of diabetic animals that received repeated doses of exosomes. Immunohistochemistry analysis also confirmed the presence of insulin in the islets of treated animals. Further investigations proposed that exosomes induce the islet regeneration through pancreatic and duodenal homeobox 1 pathway. The exosome tracking also revealed the homing of injected exosomes to the pancreas.

Aim: Proper healing of extensive burns remains a healthcare challenge. In the present study, we proposed a distinct therapeutic application of adipose tissue and small extracellular vesicles isolated from human menstrual blood-derived mesenchymal stem cells (MenSC) small extracellular vesicles (sEVs) to enhance the repair of third-degree burn injury. Materials & methods: Mouse model of third-degree burn was used. Adipose tissue in the form of nano-fat (NF) and MenSC-sEVs was injected subcutaneously at the site of injuries. Results: NF and sEVs were capable of enhancing wound closure and increasing neoangiogenesis. NF was also effective in accelerating the formation of granulation tissue and boosting the thickness of the new epithelial layer. Conclusion: This study demonstrates the effectiveness of NF and MenSC-sEVs as promising therapeutic approaches to facilitate the repair of skin burns.

Background. Recombinant proteins and growth factors are emerging therapies for diabetic foot ulcers. Despite several clinical reports, there has been no comprehensive and systematic assessment of the totality of clinical evidence on the efficacy and safety of recombinant proteins and growth factors in diabetic foot ulcers. We tried to address this gap through an updated systematic review of randomized controlled trials (RCTs).Methods. PubMed, the Cochrane Library, Scopus, Embase, and Google Scholar databases were searched, and RCTs on the efficacy of recombinant proteins and growth factors in the treatment of cutaneous wounds in diabetic patients were selected. The literature search and assessment were performed by two independent reviewers. Methodological quality of studies was appraised using the Jadad scale.Results. We identified 26 RCTs involving diabetic patients with ulcer that evaluated the effectiveness of platelet-derived growth factor, epidermal growth factor, fibroblast growth factor, granulocyte colony-stimulating factor, vascular endothelial growth factor, erythropoietin, transforming growth factor, talactoferrin, and rusalatide acetate. The main primary outcome was complete healing though different indices were employed to define this such as wound closure, granulation tissue formation, or complete reepithelialization. Few studies had a follow-up period to report any recurrence and amputation rate. No adverse effect was reported due to the intervention.Conclusion. Overall, there is a greater agreement on the effectiveness of EGF to enhance the healing of diabetic ulcers. Nevertheless, extant evidence is lacking for other agents since few trials have been conducted for most of the growth factors and available studies are heterogeneous in their methodologies.

Stroke, as the second most common cause of death, imposes a great financial burden on both the individual and society. Mesenchymal stem cells from rodents have demonstrated efficacy in experimental animal models of stroke due to enhanced neurological recovery. Since FGF1 (fibroblast growth factor 1) displays neuroprotective properties, for the first time, we investigated the effect of acute intravenous administration of FGF1 gene transfected adipose-derived mesenchymal stem cell (AD-MSCFGF1) on transient experimental ischemic stroke in rats. Stroke induction was made by transient middle cerebral artery occlusion (tMCAO). 2 × 106 AD-MSCFGF1 was administrated intravenously 30 min after carotid reperfusion. The ability of technetium99m-hexamethyl propylene amine oxime (99mTc-HMPAO)-labeled AD-MSCFGF1 to enter into ischemic brain was evaluated 2 h post injection. 24 h post operation, the neurological recovery (rotarod and Roger's tests), the infarct volume (2, 3, 5-triphenyltetrazolium chloride, TTC assay), apoptosis rate (TUNEL assay), and the expression of FGF1 protein (western blotting) in the ischemic hemisphere were assessed. The 99mTc-HMPAO-labeled AD-MSCFGF1 could enter into the ischemic brain. Ischemic hemisphere activity was significantly higher than that observed in the contralateral hemisphere (p = 0.002). The administration of AD-MSCFGF1 resulted in significant improvement of neurological function tests and increased density of FGF1 protein in the peri-infarct area, while the infarct volume and the apoptotic index were significantly decreased, in comparison to the other treated groups. In conclusion, acute intravenous administration of AD-MSCFGF1 can be a novel and promising candidate approach for the treatment of ischemic stroke.

Diabetes, as a fast growing non-communicable disease, is one of the major health problems of the twenty-first century. Several complications such as cardiovascular disease and renal failure are accompanying diabetes. The chronic cutaneous wound is another diabetes complication, results from the reduced body healing potential. At genome level, diabetic wound environment displays disorganized gene functions emphasizing the critical role of gene regulatory networks in the control of chronic wound repair. MicroRNAs, major regulators of gene activity, have been shown to be impaired in several pathological conditions such as chronic wounds. A reason behind that can be sought in the impaired activity of enzymes involved in the development and production of miRNAs. In current study, streptozocin-induced diabetic rats and non-diabetic controls were used to study the effect of diabetes on Dicer presence in wound environment. Unwounded skin of diabetic animals showed significantly lower level of Dicer expression compared with non-diabetic animal-derived skin. However, at day 7 post-wounding, diabetic animal-derived wounds contained a higher level of Dicer expression compared with non-diabetic ones. Parallel to these findings, the granulation tissue formation and wound closure are impaired in diabetic wounds. This study highlights the dysregulated presence of Dicer at different stages of the diabetic cutaneous wound.

Melanosomes are melanin-containing organelles that provide pigmentation and protection from solar UV radiation to the skin. In melanocytes, melanosomes mature and traffic to dendritic tips, where they are transferred to adjacent epidermal keratinocytes through pathways that involve microtubule networks and the actin cytoskeleton. However, the role of scaffold proteins in these processes is poorly understood. Integrin-linked kinase (ILK) is a scaffold protein that regulates microtubule stability and F-actin dynamics. Here we show that ILK is necessary for normal trafficking of melanosomes along microtubule tracks. In the absence of ILK, immature melanosomes are not retained in perinuclear regions, and mature melanosome trafficking along microtubule tracks is impaired. These deficits can be attenuated by microtubule stabilization. Microtubules are also necessary for the formation of dendrites in melanocytes, and Ilk inactivation reduces melanocyte dendricity. Activation of glycogen synthase kinase-3 (GSK-3) interferes with microtubule assembly. Significantly, inhibition of GSK-3 activity or exogenous expression of the GSK-3 substrate collapsin response mediator protein 2 (CRMP2) in ILK-deficient melanocytes restored dendricity. ILK is also required for normal melanin transfer, and GSK-3 inhibition in melanocytes partially restored melanin transfer to neighboring keratinocytes. Thus, our work shows that ILK is a central modulator of melanosome movements in primary epidermal melanocytes and identifies ILK and GSK-3 as important modulators of melanin transfer to keratinocytes, a key process for epidermal UV photoprotection.

Cell-based delivery system is a promising strategy to protect therapeutic agents from the immune system and provide targeted delivery. Mesenchymal stem cells (MSCs) have recently been introduced as an encouraging vehicle in cell-based gene therapy due to their unique features including tumor-tropic property and migratory ability. However, gene transfer into MSCs is limited due to low efficiency and cytotoxicity of carriers. In this study, we designed a novel delivery system based on polyethylenimine (PEI25 ) to improve these features of carrier and transfect plasmid encoding TRAIL to MSCs. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand of TNF family with selective effect on cancerous cells. Then, death induction and migration ability of TRAIL-expressing MSCs was studied in melanoma cells. The effect of engineered-MSCs as an antitumor vehicle was also investigated in mice bearing melanoma cells. Our findings indicated that heterocyclic amine derivative of PEI25 showed significant improvement in MSCs viability determined by MTT assay and gene expression using fluorescent microscopy, flow cytometry, and Western blot analysis. We observed that engineered-MSCs could migrate toward and induce cell death in B16F0 cells in vitro. The single administration of TRAIL-expressing MSCs could delay tumor appearance and efficiently reduce tumor weights. Hematoxylin and eosin staining of tumor sections revealed extensive neoplastic cells necrosis. Furthermore, engineered-MSCs could migrate and localize to tumors sites within 5 days. Our results indicated that MSCs engineered by modified-PEI/TRAIL complexes could be considered as a promising cellular vehicle for targeted tumor suppression.

A growing body of evidence has shown that extracellular vesicles can be efficient as experimental therapeutics in pre-clinical models of skin wounds, but there is a significant unmet need to translate this to clinical utilization. The objectives of the current systematic review were to identify the strength of the therapeutic effects of EVs derived from stem cells in cutaneous wounds and to assess which EV-mediated mechanisms could be involved in the therapeutic response. PubMed, ISI Web of Science, and Scopus databases were systematically searched. We retrieved English-language articles published through June 2020. In vivo studies which applied stem cell-derived EVs were included for further analysis. The Risk of bias was assessed by the SYRCLE tool. We identified thirty-nine pre-clinical studies that evaluated the effects of EVs on the wound healing process. The included studies varied greatly in EVs isolation techniques, route of administration, EVs producing cells, and follow-up time. In vivo application revealed beneficial effects of EVs on accelerating wound closure and re-epithelialization in a dose-dependent manner. Elevated angiogenesis was reported in twelve eligible studies through multiple signaling pathways such as PI3K/Akt, MAPK/ERK, and JAK/STAT. The well-known signaling pathway to inhibit scar formation was TGF-β2/SMAD2. However, all included studies were not blinded enough which may have introduced bias. Therefore, the transition of EV's efficacy into the clinics is deeply rooted in the following important factors: 1) pre-clinical studies with a lower risk of bias and longer follow-up time, and 2) consistent, reproducible, and feasible manufacturing of EVs production in a large-scale commercial program.

The in vitro amplification of endothelial progenitor cells (EPCs) is an important method because of its role in gene transferring and regenerative medicine. In this study, we isolated rabbit bone marrow-derived EPCs to further manipulation and overexpression of dimethylarginine dimethylaminohydrolase (DDAH) in EPCs. Isolated EPCs were cultured, expanded in endothelial basal medium. Morphology of EPCs and expression levels of surface markers detected using immunocytochemistry staining and through the use of flow cytometery. Endothelial progenitor cells were transfected with plasmid vectors expressing human DDAH2 (DDAH2-EPCs). Three days after gene transfer, positive transfected-EPCs proliferation and DDAH activity were assayed. We observed colonies conformation and endothelium-like morphology gradually in the third week of culture. Characterization results revealed positive expression of EPC surface markers CD106, Flk-1, vWF, and CD34 using few identification techniques. Overexpression of DDAH2 increased citrulline production after 96 hours of transfection, 235.34 ± 0.69 vs 95.26 ± 5.76 ng/mL; P = .023. These results suggest that cell population with EPC characteristics can be simply isolated from rabbit bone marrow and successfully engineered to overexpress exogenous gene. In this study, we offer a feasible method to isolate and identify EPCs from bone marrow. In addition, an efficient transfection with a plasmid vector (without risk of interference) can be constructed a hybrid structure with EPC and DDAH2 gene to examine their function in vitro.

The main goal of the present study is to compare the serum pro- and anti-inflammatory cytokines and growth factor profile (IL-1α, IL-1β, IL-2, IL-6, IL-8, IFN-γ, MCP-1, TNF-α, IL-10, IL-4, VEGF, and EGF) in individuals with diabetes or pre-diabetes and control subjects matched for age and gender. This study included 270 normal control subjects, 41 pre-diabetics, and 104 diabetic subjects. Demographic and anthropometric characteristics and serum biochemistry parameters, smoking status, and blood pressure were determined. Serum cytokine and growth factor measurements were performed using a multiplex biochip array based method. After removing the effects of confounders such as age, sex, smoking, BMI, serum triglyceride and cholesterol, hypertension, and treatment with anti-diabetic drugs, serum IL-4 (p = 0.015), IL-1α (p = 0.031), and VEGF (p = 0.012) were significantly associated with the presence of diabetes mellitus. The presence of pre-diabetes was positively associated with serum IL-4 (p

Background Obesity is associated with a state of systemic inflammation, mediated by adipose tissue-derived cytokines that may also have metabolic effects, including an effect on insulin resistance. The aim of this study was to compare the serum profile of pro- and anti-inflammatory cytokines in obese and non-obese subjects. Methods A total of 242 subjects who were either overweight or obese (body mass index [BMI] ≥ 25 kg/m2) and non-obese subjects (body mass index 2), were recruited in Mashhad in northeastern Iran. The concentrations of serum interleukin-1α, -1β, -2, -4, -6, -8 and -10 (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8 and IL-10), were measured in all subjects, together with serum vascular endothelial growth factor, interferon-γ, epidermal growth factor, monocyte chemoattractant protein-1 and tumour necrosis factor-α. Results The groups differed significantly with respect to measures of adiposity and fasted lipid profile. Serum pro-inflammatory cytokines interferon-γ and interleukin-1α, and anti-inflammatory cytokines, interleukin-10, and epidermal growth factor were significantly different between obese and non-obese individuals, as was serum high-sensitivity C-reactive protein. Multivariate regression showed that waist circumference was significantly and independently related to serum monocyte chemoattractant protein-1concentrations ( P = 0.001). Conclusion Despite significant differences in several cytokines between the groups, only monocyte chemoattractant protein-1appeared to be independently related to a measure of adiposity in this population sample from Iran.

Wound healing is a complicated process that contains a number of overlapping and consecutive phases, disruption in each of which can cause chronic nonhealing wounds. In the current study, we investigated the effects of exosomes as paracrine factors released from menstrual blood-derived mesenchymal stem cells (MenSCs) on wound-healing process in diabetic mice. The exosomes were isolated from MenSCs conditioned media using ultracentrifugation and were characterized by scanning electron microscope and western blotting assay. A full thickness excisional wound was created on the dorsal skin of each streptozotocin-induced diabetic mouse. The mice were divided into three groups as follows: phosphate buffered saline, exosomes, and MenSC groups. We found that MenSC-derived exosomes can resolve inflammation via induced M1-M2 macrophage polarization. It was observed that exosomes enhance neoangiogenesis through vascular endothelial growth factor A upregulation. Re-epithelialization accelerated in the exosome-treated mice, most likely through NF-κB p65 subunit upregulation and activation of the NF-κB signaling pathway. The results demonstrated that exosomes possibly cause less scar formation through decreased Col1:Col3 ratio. These notable results showed that the MenSC-derived exosomes effectively ameliorated cutaneous nonhealing wounds. We suggest that exosomes can be employed in regenerative medicine for skin repair in difficult-to-heal conditions such as diabetic foot ulcer.

Scaffold-based tissue engineering is considered as a promising approach in the regenerative medicine. Graft instability of collagen, by causing poor mechanical properties and rapid degradation, and their hard handling remains major challenges to be addressed. In this research, a composite structured nano-/microfibrous scaffold, made from a mixture of chitosan-s-glycerol phosphate-gelatin (chitosan-GP-gelatin) using a standard electrospinning set-up was developed. Gelatin-acid acetic and chitosan s-glycerol phosphate-HCL solutions were prepared at ratios of 30/70, 50/50, 70/30 (w/w) and their mechanical and biological properties were engineered. Furthermore, the pore structure of the fabricated nanofibrous scaffolds was investigated and predicted using a theoretical model. Higher gelatin concentrations in the polymer blend resulted in significant increase in mean pore size and its distribution. Interaction between the scaffold and the contained cells was also monitored and compared in the test and control groups. Scaffolds with higher chitosan concentrations showed higher rate of cell attachment with better proliferation property, compared with gelatin-only scaffolds. The fabricated scaffolds, unlike many other natural polymers, also exhibit non-toxic and biodegradable properties in the grafted tissues. In conclusion, the data clearly showed that the fabricated biomaterial is a biologically compatible scaffold with potential to serve as a proper platform for retaining the cultured cells for further application in cell-based tissue engineering, especially in wound healing practices. These results suggested the potential of using mesoporous composite chitosan-GP-gelatin fibrous scaffolds for engineering three-dimensional tissues with different inherent cell characteristics.

Background Mesenchymal stem cells (MSCs) are currently the most promising candidates in regenerative medicine. Nonetheless, there are several limitations associated with the MSC tissue source such as infrequent and invasive bone marrow sampling methods. To overcome these limitations, we have procured MSCs from the menstrual blood (MenSCs) as a non-invasive source using a straightforward and cost-effective method. Moreover, we isolated MenSCs-derived exosomes as a safe and highly effective approach to exert the paracrine effects of MSCs. Methods MSCs were isolated from menstrual blood through two different culture methods: ficoll-isolated mononuclear cells (MNCs) and whole blood culture. These cells were characterized by their plastic adherence, flow cytometry analysis of the surface markers and the differentiation potential. The exosomes were isolated from conditioned media using ultracentrifugation and characterized by different microscopy techniques, western blotting, and ELISA. Results Both Methods resulted in the rapid isolation of cells with MSC properties. However, the cellular yield of the whole blood culture method was remarkably more than MNCs culture. MenSCs also produced a substantial amount of extracellular vesicles (EVs) possessed the minimum criteria for exosome definition. Conclusion The results suggest that direct culture of whole menstrual blood cells is a high throughput, straightforward and cost-effective method for MenSCs isolation using no special growth factors. Moreover, these cells are a good producer of exosome which can offer a cell-free therapy approach.

Stroke, as the second most common cause of death, imposes a great financial burden on both the individual and society. Mesenchymal stem cells from rodents have demonstrated efficacy in experimental animal models of stroke due to enhanced neurological recovery. Since FGF1 (fibroblast growth factor 1) displays neuroprotective properties, for the first time, we investigated the effect of acute intravenous administration of FGF1 gene transfected adipose-derived mesenchymal stem cell (AD-MSC

Angiogenesis, or the growth of new blood vessels, is critical to both health and disease. Several genes are implicated in the regulation of angiogenesis, such as genes encoding growth factors, cytokines, and the extracellular matrix, as well as transcription factors. Among them, Hox genes exert master regulatory effects on several aspects of angiogenesis. The mechanism by which Hox genes are controlled is not well understood. However, recently microRNAs (miRNAs) have been introduced as candidates for Hox gene regulation. This review provides a comprehensive description of Hox genes and miRNAs involved in angiogenesis and presents possible regulatory interactions between them.

The aim of this study was to investigate, for the first time, the effects of using adipose-derived mesenchymal stem cells (AD-MSCs) transfected with an episomal plasmid encoding fibroblast growth factor 1 (FGF1) (AD-MSCsFGF1), in providing the microenvironment required for angiogenic proliferation. The isolated rat AD-MSCs were positive for mesenchymal (CD29 and CD90) and negative for hematopoietic (CD34 and CD45) surface markers. Adipogenic and osteogenic differentiation of the AD-MSCs also occurred in the proper culture media. The presence of FGF1 in the conditioned medium from the AD-MSCsFGF1 was confirmed by Western blotting. G418 and PCR were used for selection of transfected cells and confirmation of the presence of FGF1 mRNA, respectively. Treatment with the AD-MSCFGF1-conditioned medium significantly increased the NIH-3T3 cell proliferation and human umbilical vein endothelial cell (HUVEC) tube formation compared to conditioned medium from nontransfected AD-MSCs (p

Bone marrow offers a valuable source of stem/progenitor cells that contribute to the repair of injured tissues. Failure in the function of these cells results in delayed or reduced tissue repair. Identification of factors that can correct these defects is critical to treating the underlying dysfunction. Notably, homeobox (Hox) transcription factors have been identified as having significant effects on BMDC behaviour, including differentiation, migration and adhesion in injured tissue, and may provide a basis for future therapies.Hox protein regulation of bone-marrow-derived cell (BMDC) differentiation, factors that influence BMDC behaviour in response to injury, the effects of the diabetic environment on BMDCs, methods that can be used to reprogramme BMDCs, and the use of Hox transcription factors to correct BMDC behaviour.Hox gene therapy has been successfully employed to change cell behaviour using ex vivo 'reprogramming' strategies overexpressing selected Hox genes in BMDCs to direct the fate of these cells to the desired cell type, promoting tissue repair.

Scaffold-based tissue engineering is considered as a promising approach in the regenerative medicine. Graft instability of collagen, by causing poor mechanical properties and rapid degradation, and their hard handling remains major challenges to be addressed. In this research, a composite structured nano-/microfibrous scaffold, made from a mixture of chitosan-ß-glycerol phosphate-gelatin (chitosan-GP-gelatin) using a standard electrospinning set-up was developed. Gelatin-acid acetic and chitosan ß-glycerol phosphate-HCL solutions were prepared at ratios of 30/70, 50/50, 70/30 (w/w) and their mechanical and biological properties were engineered. Furthermore, the pore structure of the fabricated nanofibrous scaffolds was investigated and predicted using a theoretical model. Higher gelatin concentrations in the polymer blend resulted in significant increase in mean pore size and its distribution. Interaction between the scaffold and the contained cells was also monitored and compared in the test and control groups. Scaffolds with higher chitosan concentrations showed higher rate of cell attachment with better proliferation property, compared with gelatin-only scaffolds. The fabricated scaffolds, unlike many other natural polymers, also exhibit non-toxic and biodegradable properties in the grafted tissues. In conclusion, the data clearly showed that the fabricated biomaterial is a biologically compatible scaffold with potential to serve as a proper platform for retaining the cultured cells for further application in cell-based tissue engineering, especially in wound healing practices. These results suggested the potential of using mesoporous composite chitosan-GP-gelatin fibrous scaffolds for engineering three-dimensional tissues with different inherent cell characteristics.

Background: Severe depression may be accompanied by immune dysregulation and is also associated with increased risk of coronary artery disease (CAD). Objectives: We investigated serum levels of 10 cytokines and their relationship with depression in patients with cardiovascular diseases as well as healthy subjects in northeast of Iran. Patients and Methods: The study was carried out on 462 subjects (120 healthy subjects and 342 candidates undergoing angiography). The healthy subjects were referred for routine annual checkups or pre-employment examinations; they did not have clinically evident CAD. A questionnaire was used to obtain demographic data and the Beck depression inventory (BDI) was applied to assess depression. The Evidence Investigator ® platform was used for cytokines assays for IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, MCP-1 and IFN-γ, using sandwich chemiluminescent method. The statistical analysis was performed using SPSS version 11.5. Results: The mean age was 53.3 ± 11.5, 54.8 ± 11.3, and 59.5 ± 11.3 in healthy, angiography (-), and angiography (+) subjects, respectively (P < 0.05). There were significant differences in serum levels of IL-4, IL-6, IL-10, and MCP-1 cytokines, comparing subjects with CAD and healthy persons (P < 0.05). When all subjects were divided to with and without depression regardless of their cardiovascular status, there was a significant difference in serum levels of IL-8 and IL-6 between the groups (P < 0.05). When the subgroup with features of CAD was selected and divided to those with and without depression, there was also a significant difference in serum levels of IL-8 and TNF- α (P < 0.05). Conclusions: The positive interaction between depression and CAD was probably mediated by inflammatory mechanisms.

Analysis of tissue repair and regeneration in a variety of organisms has demonstrated that stem and progenitor cells play a critical role in the healing and regenerative response. In particular, during cutaneous wound healing bone marrow-derived cells are recruited to the site of injury in large numbers, often comprising over 50% of the cells within the wound milieu. These bone marrow-derived cells are comprised mostly of a heterogeneous mix of myeloid cells. In the early stages of wound healing, the most prominent subtypes are Gr-1(+)CD11b(+) cells that consist of progenitor cells and more differentiated granulocytes. Under certain conditions, these cells have the potential to strongly promote angiogenesis, and thus tissue repair and regeneration. This chapter provides methods by which one can isolate these cells from wound tissue and assess their pro-angiogenic capacity via gene expression analyses and functional in vivo angiogenesis assays.

Injury induces the recruitment of bone marrow-derived cells (BMDCs) that contribute to the repair and regeneration process. The behavior of BMDCs in injured tissue has a profound effect on repair, but the regulation of BMDC behavior is poorly understood. Aberrant recruitment/retention of these cells in wounds of diabetic patients and animal models is associated with chronic inflammation and impaired healing. BMD Gr-1+CD11b+ cells function as immune suppressor cells and contribute significantly to tumor-induced neovascularization. Here we report that Gr-1+CD11b+ cells also contribute to injury-induced neovascularization, but show altered recruitment/retention kinetics in the diabetic environment. Moreover, diabetic-derived Gr-1+CD11b+ cells fail to stimulate neovascularization in vivo and have aberrant proliferative, chemotaxis, adhesion, and differentiation potential. Previously we demonstrated that gene transfer of HOXA3 to wounds of diabetic mice is taken up by and expressed by recruited BMDCs. This is associated with a suppressed inflammatory response, enhanced neovascularization, and accelerated wound healing. Here we show that sustained expression of Hoxa3 in diabetic-derived BMD Gr-1+CD11b+ cells reverses their diabetic phenotype. These findings demonstrate that manipulation of adult stem/progenitor cells ex vivo could be used as a potential therapy in patients with impaired wound healing.

Stem cells are cells with the ability to divide for indefinite periods and to give rise to specialized cells. Stem cell therapy has now been emerged as an extraordinary promise to treat a wide range of diseases and conditions. However, except blood stem cell transfer by bone marrow transplant which has been used as an standard practice for more than 50 years, nearly all of therapeutic potentials of stem cell are in early stages and experimental. A lot of work still is needed to turn this research into safe and effective treatments. In addition, as stem cell research becomes closer to new medical practices, new ethical questions must be resolved by researchers. Here a short discussion has been provided on some of these stem cell hypes and worries. Keyword: Cell therapy, Stem Cell.