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Renal Ischemia-Reperfusion Injury in a Diabetic Monkey Model and Therapeutic Testing of Human Bone Marrow-Derived Mesenchymal Stem Cells.

ABSTRACT: Clinically, acute kidney injury (AKI) episodes in diabetes mellitus (DM) patients are associated with a cumulative risk of developing end-stage renal disease. In this study, we asked whether the severity of AKI induced by renal ischemia-reperfusion injury (IRI) is more prominent in DM than in non-DM control using a cynomolgus monkey (Macaca fascicularis) model. We also investigated whether human bone marrow-derived mesenchymal stem cells (hBM-MSCs) infused via the renal artery could ameliorate renal IRI in DM monkeys. The experimental data, including mortality rate, histologic findings, and urinary albumin secretion indicate that the severity of AKI was greater in DM monkeys than in control animals. Moreover, histological findings and qRT-PCR analysis of Ngal mRNA in renal biopsy tissue showed that hBM-MSC promoted the recovery of tubular damage caused by AKI. Serum analysis also revealed that the level of albumin and ALT was increased 24 and 48 hours after AKI, respectively, suggesting that AKI induced acute liver injury. We suggest that this nonhuman primate model could provide essential information about the renal and nonrenal impairment related to DM and help determine the clinical usefulness of MSCs in AKI.

SUBMITTER: Lee KW

PROVIDER: S-EPMC6092988 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Bone marrow-derived cells can acquire renal stem cells properties and ameliorate ischemia-reperfusion induced acute renal injury.

Project description:BackgroundBone marrow (BM) stem cells have been reported to contribute to tissue repair after kidney injury model. However, there is no direct evidence so far that BM cells can trans-differentiate into renal stem cells.MethodsTo investigate whether BM stem cells contribute to repopulate the renal stem cell pool, we transplanted BM cells from transgenic mice, expressing enhanced green fluorescent protein (EGFP) into wild-type irradiated recipients. Following hematological reconstitution and ischemia-reperfusion (I/R), Sca-1 and c-Kit positive renal stem cells in kidney were evaluated by immunostaining and flow cytometry analysis. Moreover, granulocyte colony stimulating factor (G-CSF) was administrated to further explore if G-CSF can mobilize BM cells and enhance trans-differentiation efficiency of BM cells into renal stem cells.ResultsBM-derived cells can contribute to the Sca-1(+) or c-Kit(+) renal progenitor cells population, although most renal stem cells came from indigenous cells. Furthermore, G-CSF administration nearly doubled the frequency of Sca-1+ BM-derived renal stem cells and increased capillary density of I/R injured kidneys.ConclusionsThese findings indicate that BM derived stem cells can give rise to cells that share properties of renal resident stem cell. Moreover, G-CSF mobilization can enhance this effect.

| S-EPMC3505151 | biostudies-literature

Mesenchymal stromal cells in renal ischemia/reperfusion injury.

Project description:Ischemia/reperfusion (I/R) injury is an inevitable consequence of organ transplantation and a major determinant of patient and graft survival in kidney transplantation. Renal I/R injury can lead to fibrosis and graft failure. Although the exact sequence of events in the pathophysiology of I/R injury remains unknown, the role of inflammation has become increasingly clear. In this perspective, mesenchymal stromal cells (MSCs) are under extensive investigation as potential therapy for I/R injury, since MSCs are able to exert immune regulatory and reparative effects. Various preclinical studies indicate the beneficial effects of MSCs in ameliorating renal injury and accelerating tissue repair. These versatile cells have been shown to migrate to sites of injury and to enhance repair by paracrine mechanisms instead of by differentiating and replacing the injured cells. The first phase I studies of MSCs in human renal I/R injury and kidney transplantation have been started, and results are awaited soon. In this review, preliminary results and opportunities of MSCs in human renal I/R injury are summarized. We might be heading towards a cell-based paradigm shift in the treatment of renal I/R injury.

| S-EPMC3387652 | biostudies-literature

Extracellular vesicles from bone marrow-derived mesenchymal stem cells protect against murine hepatic ischemia/reperfusion injury.

Project description:Hepatic ischemia/reperfusion injury (IRI) and associated inflammation contributes to liver dysfunction and complications after liver surgery and transplantation. Mesenchymal stem cells (MSCs) have been reported to reduce hepatic IRI because of their reparative immunomodulatory effects in injured tissues. Recent studies have highlighted beneficial effects of extracellular vesicles from mesenchymal stem cells (MSC-EV) on tissue injury. The effects of systemically administered mouse bone marrow-derived MSC-EV were evaluated in an experimental murine model of hepatic IRI induced by cross-clamping the hepatic artery and portal vein for 90 minutes followed by reperfusion for periods of up to 6 hours. Compared with controls, intravenous administration of MSC-EV 30 minutes prior to IRI dramatically reduced the extent of tissue necrosis, decreased caspase 3-positive and apoptotic cells, and reduced serum aminotransferase levels. MSC-EV increased hepatic messenger RNA (mRNA) expression of NACHT, LRR, and PYD domains-containing protein 12, and the chemokine (C-X-C motif) ligand 1, and reduced mRNA expression of several inflammatory cytokines such as interleukin 6 during IRI. MSC-EV increased cell viability and suppressed both oxidative injury and nuclear factor kappa B activity in murine hepatocytes in vitro. In conclusion, the administration of extracellular vesicles derived from bone marrow-derived MSCs may ameliorate hepatic IRI by reducing hepatic injury through modulation of the inflammatory response.Liver Transplantation 23 791-803 2017 AASLD.

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Bone marrow-derived mesenchymal stem cells attenuate myocardial ischemia-reperfusion injury via upregulation of splenic regulatory T cells.

Project description:BackgroundMyocardial ischemia-reperfusion injury (MIRI) is the main pathological manifestation of cardiovascular diseases such as myocardial infarction. The potential therapeutic effects of bone marrow-derived mesenchymal stem cells (BM-MSCs) and the participation of regulatory T cells (Tregs) in MIRI remains to be defined.MethodsWe used the experimental acute MIRI that was induced in mice by left ascending coronary ischemia, which were subsequently randomized to receive immunoglobulin G (IgG) or anti-CD25 antibody PC61 with or without intravenously injected BM-MSCs. The splenectomized mice underwent prior to experimental MIRI followed by intravenous administration of BM-MSCs. At 72 h post-MIRI, the hearts and spleens were harvested and subjected to cytometric and histologic analyses.ResultsCD25+Foxp3+ regulatory T cells were significantly elevated after MIRI in the hearts and spleens of mice receiving IgG + BM-MSCs and PC61 + BM-MSCs compared to the respective control mice (all p < 0.01). This was accompanied by upregulation of interleukin 10 and transforming growth factor β1 and downregulation of creatinine kinase and lactate dehydrogenase in the serum. The post-MIRI mice receiving BM-MSCs showed attenuated inflammation and cellular apoptosis in the heart. Meanwhile, splenectomy compromised all therapeutic effects of BM-MSCs.ConclusionAdministration of BM-MSCs effectively alleviates MIRI in mice through inducing Treg activation, particularly in the spleen.

| S-EPMC8080373 | biostudies-literature

Therapeutic Properties of Mesenchymal Stem Cell on Organ Ischemia-Reperfusion Injury.

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| S-EPMC6862572 | biostudies-literature

Umbilical cord extracts improve diabetic abnormalities in bone marrow-derived mesenchymal stem cells and increase their therapeutic effects on diabetic nephropathy.

Project description:Bone marrow-derived mesenchymal stem cells (BM-MSC) has been applied as the most valuable source of autologous cell transplantation for various diseases including diabetic complications. However, hyperglycemia may cause abnormalities in intrinsic BM-MSC which might lose sufficient therapeutic effects in diabetic patients. We demonstrated the functional abnormalities in BM-MSC derived from both type 1 and type 2 diabetes models in vitro, which resulted in loss of therapeutic effects in vivo in diabetic nephropathy (DN). Then, we developed a novel method to improve abnormalities in BM-MSC using human umbilical cord extracts, namely Wharton's jelly extract supernatant (WJs). WJs is a cocktail of growth factors, extracellular matrixes and exosomes, which ameliorates proliferative capacity, motility, mitochondrial degeneration, endoplasmic reticular functions and exosome secretions in both type 1 and type 2 diabetes-derived BM-MSC (DM-MSC). Exosomes contained in WJs were a key factor for this activation, which exerted similar effects to complete WJs. DM-MSC activated by WJs ameliorated renal injury in both type 1 and type 2 DN. In this study, we developed a novel activating method using WJs to significantly increase the therapeutic effect of BM-MSC, which may allow effective autologous cell transplantation.

| S-EPMC5559488 | biostudies-other

Exosomes Released by Bone Marrow Mesenchymal Stem Cells Attenuate Lung Injury Induced by Intestinal Ischemia Reperfusion via the TLR4/NF-?B Pathway.

Project description:Purpose: Acute lung injury (ALI) is a primary component of multiple organ dysfunction syndromes triggered by intestinal ischemia-reperfusion (IIR) which results in high mortality. Existing treatment options remain unsatisfactory. Mesenchymal stem cells (MSCs) have shown considerable promise as a biological therapy for ALI in preclinical studies. However, there are many limitations to stem cell treatment. This study aimed to investigate whether MSC-derived exosomes, a non-cellular alternative, are able to act in a protective capacity similar to that of MSCs for ALI triggered by IIR in a rat model and to explore the underlying mechanisms. Methods: The IIR model involved occlusion of the superior mesenteric artery of a rat for 75 min then reperfusion for 20 h. Rats then received an intravenous injection of either bone marrow-derived MSCs or MSC-derived exosomes. Pathologic alteration of lung tissue, levels of pro-inflammatory cytokines, apoptotic proteins and TLR4/NF-?B signaling were measured to evaluate the therapeutic effect of treatment with either MSCs or exosomes. Results: Manifestations of acute lung injury after IIR were observed as edema and hemorrhage of alveoli and mesenchyme, and inflammatory cell infiltration. MSCs and MSC-derived exosomes both attenuated IIR-induced lung damage by decreased apoptosis and inflammation accompanied by down-regulation of TLR4 and NF-?B expression. Conclusions: MSC-derived exosomes provide protection similar to that of MSCs against IIR-induced ALI via inhibition of TLR4/NF-?B signaling, suggesting that a potential strategy against IIR-mediated acute lung injury could be therapy with exosomes as a non-cellular alternative to MSC transplantation.

| S-EPMC6775266 | biostudies-literature

Exogenous bone marrow derived-putative endothelial progenitor cells attenuate ischemia reperfusion-induced vascular injury and renal fibrosis in mice dependent on pericytes.

Project description:Rationale: Capillaries are composed of endothelial cells and the surrounding mural cells, pericytes. Microvascular repair after injury involves not only the proliferation of endothelial cells but also pericyte-based vessel stabilization. Exogenous bone marrow derived-putative endothelial progenitor cells (b-pEPCs) have the potential for vascular repair; however, their effect on vascular structure stabilization and pericyte-related pathobiological outcomes in the injured kidney has not been fully examined. Methods: We applied ischemia-reperfusion (IR) to induce renal vascular injury and renal fibrosis in mice. Platelet-derived growth factor receptor β (PDGFR-β)-DTR-positive mice were generated to deplete pericytes, and exogenous b-pEPCs and the PDGFR-β ligand, PDGF chain B (PDGF-BB), were employed to explore the relationship among b-pEPCs, pericytes, vascular repair, and early renal fibrosis. Results: Administration of b-pEPCs reduced IR-induced pericyte-endothelial detachment, pericyte proliferation, and myofibroblast transition via a paracrine mode, which preserved not only vascular stabilization but also ameliorated IR-initiated renal fibrosis. PDGF-BB upregulated the expression of PDGFR-β, exacerbated vascular abnormality, and pericyte-myofibroblast transition, which were ameliorated by b-pEPCs administration. The exogenous b-pEPCs and their culture medium (CM) induced vascular injury protection, and renal fibrosis was blocked by selective deletion of pericytes. Conclusion: Exogenous b-pEPCs directly protect against IR-induced vascular injury and prevent renal fibrosis by inhibiting the activation of PDGFR-β-positive pericytes.

| S-EPMC7667688 | biostudies-literature

Hypoxia-preconditioned mesenchymal stem cells prevent renal fibrosis and inflammation in ischemia-reperfusion rats.

Project description:BACKGROUND:Mesenchymal stem cells (MSCs) have been reported to promote the regeneration of injured tissue via their paracrine abilities, which are enhanced by hypoxic preconditioning. In this study, we examined the therapeutic efficacy of hypoxia-preconditioned MSCs on renal fibrosis and inflammation in rats with ischemia-reperfusion injury (IRI). METHODS:MSCs derived from rats and humans were incubated in 1% O2 conditions (1%O2 MSCs) for 24?h. After IRI, 1%O2 MSCs or MSCs cultured under normoxic conditions (21%O2 MSCs) were injected through the abdominal aorta. At 7 or 21?days post-injection, the rats were sacrificed and their kidneys were analyzed. In in vitro experiments, we examined whether 1%O2 MSCs enhanced the ability to produce anti-fibrotic humoral factors using transforming growth factor (TGF)-?1-stimulated HK-2 cells incubated with conditioned medium from MSCs. RESULTS:Administration of rat 1%O2 MSCs (1%O2 rMSCs) attenuated renal fibrosis and inflammation more significantly than rat 21%O2 MSCs. Notably, human 1%O2 MSCs (1%O2 hMSCs) also attenuated renal fibrosis to the same extent as 1%O2 rMSCs. Flow cytometry showed that 1%O2 hMSCs did not change human leukocyte antigen expression. Further in vitro experiments revealed that conditioned medium from 1%O2 MSCs further suppressed TGF-?1-induced fibrotic changes in HK-2 cells compared with 21%O2 MSCs. Hypoxic preconditioning enhanced vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) secretion. Interestingly, VEGF knockdown in 1%O2 MSCs attenuated HGF secretion and the inhibition of TGF-?1-induced fibrotic changes in HK-2 cells. In addition, VEGF knockdown in 1%O2 hMSCs reduced the anti-fibrotic effect in IRI rats. CONCLUSIONS:Our results indicate that hypoxia-preconditioned MSCs are useful as an allogeneic transplantation cell therapy to prevent renal fibrosis and inflammation.

| S-EPMC7083035 | biostudies-literature

Comparison of the therapeutic effects of adipose?derived and bone marrow mesenchymal stem cells on erectile dysfunction in diabetic rats.

Project description:The aim of the present study was to compare the effects of adipose?derived mesenchymal stem cell (ADSC) and bone marrow mesenchymal stem cell (BMSC) transplantation into the corpora cavernosa of diabetic rats with erectile function. ADSCs and BMSCs were isolated and identified by flow cytometry. Rats with streptozocin?induced diabetes were screened using apomorphine to obtain a rat model of diabetic erectile dysfunction, followed by transplantation of ADSCs and BMSCs into the corpora cavernosa. Two weeks later, the rats were again injected with apomorphine, the intracavernous pressure (ICP) and mean arterial pressure (MAP) of the penile tissue were measured, and the corpus cavernosum tissues were harvested. Angiogenic endothelial nitric oxide synthase (eNOS) expression was detected by western blotting and immunofluorescence analysis. The blood vessels in the corpus cavernosum were observed following hematoxylin and eosin (H&E) staining, and the expression of collagen was detected by Sirius Red staining. The cellular ultrastructure was examined by transmission electron microscopy. Intracavernous injection of ADSCs significantly increased ICP and ICP/MAP. Western blotting and immunofluorescence results revealed that ADSC treatment improved the expression of eNOS in the penile tissue of diabetic rats. The H&E staining results demonstrated that ADSC treatment promoted revascularization of the corpus cavernosum, and the results of Sirius Red staining revealed that ADSC treatment reduced penile collagen in diabetic rats. Transmission electron microscopy examination revealed that the ultrastructure of the tissues in the ADSC?treated group was more complete compared with that in the untreated diabetic model group. In conclusion, ADSCs were found to be more effective compared with BMSCs in treating diabetes?related erectile dysfunction.

| S-EPMC6658012 | biostudies-literature

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