Therapeutic angiogenesis is an important strategy to rescue ischemic tissues in patients with critical limb ischemia having no other treatment option such as endovascular angioplasty or bypass surgery. Studies indicated so far possibilities of therapeutic angiogenesis using autologous bone marrow mononuclear cells, CD34⁺ cells, peripheral blood mononuclear cells, adipose-derived stem/progenitor cells, and etc. Recent studies indicated that subcutaneous adipose tissue contains stem/progenitor cells that can give rise to several mesenchymal lineage cells. Moreover, these mesenchymal progenitor cells release a variety of angiogenic growth factors including vascular endothelial growth factor, fibroblast growth factor, hepatocyte growth factor and chemokine stromal cell-derived factor-1. Subcutaneous adipose tissues can be harvested by less invasive technique. These biological properties of adipose-derived regenerative cells (ADRCs) implicate that autologous subcutaneous adipose tissue would be a useful cell source for therapeutic angiogenesis in humans. In this review, I would like to discuss biological properties and future perspective of ADRCs-mediated therapeutic angiogenesis.
Angioplasty ; Bone Marrow ; Extremities ; Fibroblast Growth Factors ; Hepatocyte Growth Factor ; Humans ; Intercellular Signaling Peptides and Proteins ; Ischemia ; Mesenchymal Stromal Cells ; Stem Cell Transplantation ; Stem Cells ; Subcutaneous Fat ; Vascular Endothelial Growth Factor A

OBJECTIVE: To explore the effect of damage of bone marrow stroma cells induced by chemotherapeutic drug on the function of normal hematopoitic cells. METHODS: Senescence cells were detected by flow cytometry after SA-β-gal staining; real-time PCR was used to detect the expression of a serial molecules in bone marrow stromal cell line OP9 cells; the expression of γ-H2AX was determined by flow cytometry after histone γ-H2AX staining; the colony forming ability of hematopoietic cells was tested by colony formation assay. RESULTS: The percentage of senescence cells in OP9 cells after DNR treatment was 2.24 times as much as that in untreated OP9 cells (P<0.05). Compared with normal OP9 cells, the expression levels of IL-6 and TNF-alpha in DNR-treated OP9 cells increased by 2.73 times (P<0.01) and 0.56 times (P<0.01), and the expression levels of N-cadherin, alpha smooth muscle actin (alpha-SMA), angiopoietin1 (Angpt1) and osteopontin (OPN) decreased by 69.54%（P<0.01），63.90%（P<0.01），87.41%（P<0.01）and 42.78%（P<0.01）respectively. After the co-culture with DNR-treated OP9 cells, the colony formation of normal hematopoietic cells decreased by 47.10% than that co-cultured with untreated OP9 cells (P< 0.05), meanwhile, the percentage of γ-H2AX+ cells in normal hematopoietic cells increased by 2.19 times (P<0.05). CONCLUSION After treatment with DNR, the senescence cell number of OP9 cells sgnificantly increases; the expression of TNF-α and IL-6 is up-regulated, while the expression of α-SMA, Angpt-1 and OPN is down-regulated as compared with normal OP9 cells. In addition, after co-culture of DNR-treated OP9 cells with normal hematopoietic cells, the colony formation ability of hematopoietic cells decreases and the genome instability of hematopoietic cells increases as compared with normal hematopoietic cells.
Animals ; Bone Marrow ; Bone Marrow Cells ; Cells, Cultured ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells ; Mesenchymal Stem Cells ; Mice ; Stromal Cells

BACKGROUND: Liver disease is one of the top causes of death globally. Although liver transplantation is a very effective treatment strategy, the shortage of available donor organs, waiting list mortality, and high costs of surgery remain huge problems. Stem cells are undifferentiated cells that can differentiate into a variety of cell types. Scientists are exploring the possibilities of generating hepatocytes from stem cells as an alternative for the treatment of liver diseases. METHODS: In this review, we summarized the updated researches in the field of stem cell-based therapies for liver diseases as well as the current challenges and future expectations for a successful cell-based liver therapy. RESULTS: Several cell types have been investigated for liver regeneration, such as embryonic stem cells, induced pluripotent stem cells, liver stem cells, mesenchymal stem cells, and hematopoietic stem cells. In vitro and in vivo studies have demonstrated that stem cells are promising cell sources for the liver regeneration. CONCLUSION: Stem cell-based therapy could be a promising therapeutic method for patients with end-stage liver disease, which may alleviate the need for liver transplantation in the future.
Cause of Death ; Embryonic Stem Cells ; Hematopoietic Stem Cells ; Hepatocytes ; Humans ; In Vitro Techniques ; Induced Pluripotent Stem Cells ; Liver Diseases ; Liver Regeneration ; Liver Transplantation ; Liver ; Mesenchymal Stromal Cells ; Methods ; Mortality ; Stem Cells ; Tissue Donors ; Waiting Lists

BACKGROUND AND OBJECTIVES: In regenerative medicine, mesenchymal stem cells derived from adipose tissues (Ad-MSCs) are a very attractive target to treat many diseases. In relation to nephrology, the aim of the current study is to investigate the effects of Ad-MSCs for the amelioration of acute kidney injury and to explore the mechanism of renal parenchymal changes in response to allogeneic transplantation of Ad-MSCs. METHODS AND RESULTS: The nephrotoxicity was induced by cisplatin (CP) in balb/c mice according to RIFLE Class and AKIN Stage 3. PCR, qRT-PCR and fluorescent labeled cells infusion, histopathology, immunohistochemistry, functional analyses were used for genes and proteins expressions data acquisition respectively. We demonstrated that single intravenous infusion of 2.5×107/kg mAd-MSCs in mice pre-injected with CP recruited to the kidney, restored the renal structure, and function, which resulted in progressive survival of mice. The renal tissue morphology was recovered in terms of diminished necrosis or epithelial cells damage, protein casts formation, infiltration of inflammatory cells, tubular dilatation, and restoration of brush border protein; Megalin and decreased Kim-1 expressions in mAd-MSCs transplanted mice. Significant reduction in serum creatinine with slashed urea and urinary protein levels were observed. Anti-BrdU staining displayed enhanced tubular cells proliferation. Predominantly, downgrade expressions of TNF-α and TGF-β1 were observed post seven days in mAd-MSCs transplanted mice. CONCLUSIONS: Ad-MSCs exerts pro-proliferative, anti-inflammatory, and anti-fibrotic effects. Ad-MSCs transplantation without any chemical or genetic manipulation can provide the evidence of therapeutic strategy for the origin of regeneration and overall an improved survival of the system in functionally deprived failed kidneys.
Acute Kidney Injury ; Animals ; Cisplatin ; Creatinine ; Dilatation ; Epithelial Cells ; Immunohistochemistry ; Infusions, Intravenous ; Kidney ; Low Density Lipoprotein Receptor-Related Protein-2 ; Mesenchymal Stromal Cells ; Mice ; Microvilli ; Necrosis ; Nephrology ; Polymerase Chain Reaction ; Regeneration ; Regenerative Medicine ; Transplantation, Homologous ; Urea

BACKGROUND AND OBJECTIVES: Treatment with mesenchymal stem cells (MSC) in spinal cord injury (SCI) has been highlighted as therapeutic candidate for SCI. Although astrogliosis is a major phenomenon after SCI, the role of astrogliosis is still controversial. In this study, we determined whether acute transplantation of MSC improves the outcome of SCI through modulating astrogliosis. METHODS: Bone marrow derived rat MSCs were induced neural differentiation and transplanted after acute SCI rats. Matrix metalloproteinase (MMP) and neuro-inflammatory pathway were analyzed for acute astrogliosis at 1, 3 and 7 d after SCI in RT-PCR- and western blot analysis. Functional outcome was assessed serially at postoperative 1 d and weekly for 4 weeks. Histopathologic analysis was undertaken at 7 and 28 d following injury in immunohistochemistry. RESULTS: Transplantation of MSCs decreased IL-1α, CXCL-2, CXCL-10, TNF-α and TGF-β in a rat model of contusive SCI. Protein level of NF-κB p65 was slightly decreased while level of STAT-3 was increased. In immunohistochemistry, MSC transplantation increased acute astrogliosis whereas attenuated scar formation with increased sparing white matter of spinal cord lesions. In RT-PCR analysis, mRNA levels of MMP2 was significantly increased in MSC transplanted rats. In BBB locomotor scale, the rats of MSC treated group exhibited improvement of functional recovery. CONCLUSIONS: Transplantation of MSC reduces the inflammatory reaction and modulates astrogliosis via MMP2/STAT3 pathway leading to improve functional recovery after SCI in rats.
Animals ; Blotting, Western ; Bone Marrow ; Cicatrix ; Immunohistochemistry ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stromal Cells ; Models, Animal ; Rats ; RNA, Messenger ; Spinal Cord Injuries ; Spinal Cord ; White Matter

Inflammatory bowel disease (IBD) is an idiopathic, multi-etiological disease characterized by inflammation and mucosal destruction of the gastrointestinal tract. Despite the remarkable advance in immunomodulating therapies, there still remains a certain population of patients who are refractory to conventional as well as biologic therapies and fail to achieve mucosal healing. To improve the prognosis of those patients, at least 2 types of stem cells have been tested for their potential therapeutic use. Transplantation of hematopoietic stem cells or mesenchymal stem cells have been tested in several clinical studies, but their beneficial effect still remains controversial. In this review, we would like to overview the recent clinical challenges of stem cell-based therapies in IBD and also introduce our new therapeutic plan of intestinal stem cell transplantation for IBD, based on our ex vivo intestinal organoid culture technique.
Biological Therapy ; Culture Techniques ; Gastrointestinal Tract ; Hematopoietic Stem Cells ; Humans ; Inflammation ; Inflammatory Bowel Diseases ; Mesenchymal Stromal Cells ; Organoids ; Prognosis ; Stem Cell Transplantation ; Stem Cells

OBJECTIVE: Spinal cord injury (SCI) is a very serious health problem, usually caused by a trauma and accompanied by elevated levels of inflammation indicators. Stem cell-based therapy is promising some valuable strategies for its functional recovery. Nestin-positive progenitor and/or stem cells (SC) isolated from pancreatic islets (PI) show mesenchymal stem cell (MSC) characteristics. For this reason, we aimed to analyze the effects of rat pancreatic islet derived stem cell (rPI-SC) delivery on functional recovery, as well as the levels of inflammation factors following SCI.METHODS: rPI-SCs were isolated, cultured and their MSC characteristics were determined through flow cytometry and immunofluorescence analysis. The experimental rat population was divided into three groups : 1) laminectomy & trauma, 2) laminectomy & trauma & phosphate-buffered saline (PBS), and 3) laminectomy+trauma+SCs. Green fluorescent protein (GFP) labelled rPI-SCs were transplanted into the injured rat spinal cord. Their motilities were evaluated with Basso, Beattie and Bresnahan (BBB) Score. After 4-weeks, spinal cord sections were analyzed for GFP labeled SCs and stained for vimentin, S100β, brain derived neurotrophic factor (BDNF), 2’,3’-cyclic-nucleotide 3'-phosphodiesterase (CNPase), vascular endothelial growth factor (VEGF) and proinflammatory (interleukin [IL]-6, transforming growth factor [TGF]-β, macrophage inflammatory protein [MIP]-2, myeloperoxidase [MPO]) and anti-inflammatory (IL-1 receptor antagonis) factors.RESULTS: rPI-SCs were revealed to display MSC characteristics and express neural and glial cell markers including BDNF, glial fibrillary acidic protein (GFAP), fibronectin, microtubule associated protein-2a,b (MAP2a,b), β3-tubulin and nestin as well as antiinflammatory prostaglandin E2 receptor, EP3. The BBB scores showed significant motor recovery in group 3. GFP-labelled cells were localized on the injury site. In addition, decreased proinflammatory factor levels and increased intensity of anti-inflammatory factors were determined.CONCLUSION: Transplantation of PI-SCs might be an effective strategy to improve functional recovery following spinal cord trauma.
Animals ; Brain-Derived Neurotrophic Factor ; Dinoprostone ; Fibronectins ; Flow Cytometry ; Fluorescent Antibody Technique ; Glial Fibrillary Acidic Protein ; Inflammation ; Islets of Langerhans ; Laminectomy ; Macrophages ; Mesenchymal Stromal Cells ; Microtubules ; Nestin ; Neuroglia ; Peroxidase ; Rats ; Regeneration ; Spinal Cord Injuries ; Spinal Cord ; Stem Cell Transplantation ; Stem Cells ; Transforming Growth Factors ; Vascular Endothelial Growth Factor A ; Vimentin ; Wounds and Injuries

PURPOSE: Increased bone regeneration has been achieved through the use of stem cells in combination with graft material. However, the survival of transplanted stem cells remains a major concern. The purpose of this study was to evaluate the viability of transplanted mesenchymal stem cells (MSCs) at an early time point (24 hours) based on the type and form of the scaffold used, including type I collagen membrane and synthetic bone. METHODS: The stem cells were obtained from the periosteum of the otherwise healthy dental patients. Four symmetrical circular defects measuring 6 mm in diameter were made in New Zealand white rabbits using a trephine drill. The defects were grafted with 1) synthetic bone (β-tricalcium phosphate/hydroxyapatite [β-TCP/HA]) and 1×105 MSCs, 2) collagen membrane and 1×105 MSCs, 3) β-TCP/HA+collagen membrane and 1×105 MSCs, or 4) β-TCP/HA, a chipped collagen membrane and 1×105 MSCs. Cellular viability and the cell migration rate were analyzed. RESULTS: Cells were easily separated from the collagen membrane, but not from synthetic bone. The number of stem cells attached to synthetic bone in groups 1, 3, and 4 seemed to be similar. Cellular viability in group 2 was significantly higher than in the other groups (P<0.05). The cell migration rate was highest in group 2, but this difference was not statistically significant (P>0.05). CONCLUSIONS: This study showed that stem cells can be applied when a membrane is used as a scaffold under no or minimal pressure. When space maintenance is needed, stem cells can be loaded onto synthetic bone with a chipped membrane to enhance the survival rate.
Bone Regeneration ; Bone Transplantation ; Cell Movement ; Cell Survival ; Collagen ; Collagen Type I ; Humans ; Membranes ; Mesenchymal Stromal Cells ; Periosteum ; Rabbits ; Space Maintenance, Orthodontic ; Stem Cells ; Survival Rate ; Tissue Scaffolds ; Transplants

BACKGROUND: Cerebral Palsy (CP) is the most common motor disability reason of childhood that occurs secondarily to non-progressive damage in the brain whose development is still ongoing. METHODS: 6-year-old dystonic-spastic male CP patient received allogenic mesenchymal stem cells treatment four times as 1×106/kg in intrathecal and intravenous administration of Umbilical Cord-derived mesenchymal stem cells (UC-MSCs) ways. Before and after the treatment, the patient was followed-up with FIM (Functional Independent Measurement), GMFCS (Gross Motor Function Classification System 88), Tardieu Scale, TCMS (Trunk Control Measurement Scale), MACS (Manual Ability Classification Scale), CFSS (Communication Function Classification System) for 18 months and received intensive rehabilitation. RESULTS: Improvements were observed especially in functional scales except for the Tardieu Scale, and no adverse effects were detected aside from a slight pain in the back. CONCLUSION: Wider future case studies on UC-MSCs will enable us to assess the efficacy of UC-MSCs which have positive impacts especially on functional scales.
Administration, Intravenous ; Brain ; Cerebral Palsy ; Child ; Classification ; Humans ; Male ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stromal Cells ; Rehabilitation ; Weights and Measures

BACKGROUND AND OBJECTIVES: Glial scarring and inflammation after spinal cord injury (SCI) interfere with neural regeneration and functional recovery due to the inhibitory microenvironment of the injured spinal cord. Stem cell transplantation can improve functional recovery in experimental models of SCI, but many obstacles to clinical application remain due to concerns regarding the effectiveness and safety of stem cell transplantation for SCI patients. In this study, we investigated the effects of transplantation of human mesenchymal stem cells (hMSCs) that were genetically modified to express Olig2 in a rat model of SCI. METHODS: Bone marrow-derived hMSCs were genetically modified to express Olig2 and transplanted one week after the induction of contusive SCI in a rat model. Spinal cords were harvested 7 weeks after transplantation. RESULTS: Transplantation of Olig2-expressing hMSCs significantly improved functional recovery in a rat model of contusive SCI model compared to the control hMSC-transplanted group. Transplantation of Olig2-expressing hMSCs also attenuated glial scar formation in spinal cord lesions. Immunohistochemical analysis showed that transplanted Olig2-expressing hMSCs were partially differentiated into Olig1-positive oligodendrocyte-like cells in spinal cords. Furthermore, NF-M-positive axons were more abundant in the Olig2-expressing hMSC-transplanted group than in the control hMSC-transplanted group. CONCLUSIONS: We suggest that Olig2-expressing hMSCs are a safe and optimal cell source for treating SCI.
Axons ; Cicatrix ; Humans ; Inflammation ; Mesenchymal Stromal Cells ; Models, Animal ; Models, Theoretical ; Regeneration ; Spinal Cord Injuries ; Spinal Cord ; Stem Cell Transplantation ; Transplantation