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Pioglitazone treatment prior to transplantation improves the efficacy of human mesenchymal stem cells after traumatic brain injury in rats.

ABSTRACT: Traumatic brain injury is a leading cause of death and disability around the world. So far, drugs are not available to repair brain damage. Human mesenchymal stem cell (hMSC) transplantation therapy is a promising approach, although the inflammatory microenvironment of the injured brain affects the efficacy of transplanted hMSCs. We hypothesize that reducing the inflammation in the cerebral microenvironment by reducing pro-inflammatory chemokines prior to hMSC administration will improve the efficacy of hMSC therapy. In a rat model of lateral fluid percussion injury, combined pioglitazone (PG) and hMSC (combination) treatment showed less anxiety-like behavior and improved sensorimotor responses to a noxious cold stimulus. Significant reduction in brain lesion volume, neurodegeneration, microgliosis and astrogliosis were observed after combination treatment. TBI induced expression of inflammatory chemokine CCL20 and IL1-β were significantly decreased in the combination treatment group. Combination treatment significantly increased brain-derived neurotrophic factor (BDNF) level and subventricular zone (SVZ) neurogenesis. Taken together, reducing proinflammatory cytokine expression in the cerebral tissues after TBI by PG administration and prior to hMSC therapy improves the outcome of the therapy in which BDNF could have a role.

SUBMITTER: Das M

PROVIDER: S-EPMC6754424 | biostudies-other | 2019 Sep

REPOSITORIES: biostudies-other

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Pioglitazone treatment prior to transplantation improves the efficacy of human mesenchymal stem cells after traumatic brain injury in rats.

Das Mahasweta M Mayilsamy Karthick K Tang Xiaolan X Han Jung Yeon JY Foran Elspeth E Willing Alison E AE Mohapatra Shyam S SS Mohapatra Subhra S

Scientific reports 20190920 1

Traumatic brain injury is a leading cause of death and disability around the world. So far, drugs are not available to repair brain damage. Human mesenchymal stem cell (hMSC) transplantation therapy is a promising approach, although the inflammatory microenvironment of the injured brain affects the efficacy of transplanted hMSCs. We hypothesize that reducing the inflammation in the cerebral microenvironment by reducing pro-inflammatory chemokines prior to hMSC administration will improve the eff ...[more]

PMID: 31541141

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Project description:BackgroundStudies have shown that transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) protects against brain damage. However, the low survival number of transplanted BMSCs remains a pertinent challenge and can be attributed to the unfavorable microenvironment of the injured brain. It is well known that calpain activation plays a critical role in traumatic brain injury (TBI)-mediated inflammation and cell death; previous studies showed that inhibiting calpain activation is neuroprotective after TBI. Thus, we investigated whether preconditioning with the calpain inhibitor, MDL28170, could enhance the survival of BMSCs transplanted at 24 h post TBI to improve neurological function.MethodsTBI rat model was induced by the weight-drop method, using the gravitational forces of a free falling weight to produce a focal brain injury. MDL28170 was injected intracranially at the lesion site at 30 min post TBI, and the secretion levels of neuroinflammatory factors were assessed 24 h later. BMSCs labeled with green fluorescent protein (GFP) were locally administrated into the lesion site of TBI rat brains at 24 h post TBI. Immunofluorescence and histopathology were performed to evaluate the BMSC survival and the TBI lesion volume. Modified neurological severity scores were chosen to evaluate the functional recovery. The potential mechanisms by which MDL28170 is involved in the regulation of inflammation signaling pathway and cell apoptosis were determined by western blot and immunofluorescence staining.ResultsOverall, we found that a single dose of MDL28170 at acute phase of TBI improved the microenvironment by inhibiting the inflammation, facilitated the survival of grafted GFP-BMSCs, and reduced the grafted cell apoptosis, leading to the reduction of lesion cavity. Furthermore, a significant neurological function improvement was observed when BMSCs were transplanted into a MDL28170-preconditioned TBI brains compared with the one without MDL28170-precondition group.ConclusionsTaken together, our data suggest that MDL28170 improves BMSC transplantation microenvironment and enhances the neurological function restoration after TBI via increased survival rate of BMSCs. We suggest that the calpain inhibitor, MDL28170, could be pursued as a new combination therapeutic strategy to advance the effects of transplanted BMSCs in cell-based regenerative medicine.

Project description:BACKGROUND:Spermatogonial stem cell transplantation (SSCT) could become a fertility restoration tool for childhood cancer survivors. However, since in mice, the colonization efficiency of transplanted spermatogonial stem cells (SSCs) is only 12%, the efficiency of the procedure needs to be improved before clinical implementation is possible. Co-transplantation of mesenchymal stem cells (MSCs) might increase colonization efficiency of SSCs by restoring the SSC niche after gonadotoxic treatment. METHODS:A mouse model for long-term infertility was developed and used to transplant SSCs (SSCT, n?=?10), MSCs (MSCT, n =?10), a combination of SSCs and MSCs (MS-SSCT, n?=?10), or a combination of SSCs and TGFß1-treated MSCs (MSi-SSCT, n?=?10). RESULTS:The best model for transplantation was obtained after intraperitoneal injection of busulfan (40 mg/kg body weight) at 4 weeks followed by CdCl2 (2 mg/kg body weight) at 8 weeks of age and transplantation at 11 weeks of age. Three months after transplantation, spermatogenesis resumed with a significantly better tubular fertility index (TFI) in all transplanted groups compared to non-transplanted controls (P?<?0.001). TFI after MSi-SSCT (83.3?±?19.5%) was significantly higher compared to MS-SSCT (71.5?±?21.7%, P?=?0.036) but did not differ statistically compared to SSCT (78.2?±?12.5%). In contrast, TFI after MSCT (50.2?±?22.5%) was significantly lower compared to SSCT (P?<?0.001). Interestingly, donor-derived TFI was found to be significantly improved after MSi-SSCT (18.8?±?8.0%) compared to SSCT (1.9?±?1.1%; P?<?0.001), MSCT (0.0?±?0.0%; P?<?0.001), and MS-SSCT (3.4?±?1.9%; P?<?0.001). While analyses showed that both native and TGFß1-treated MSCs maintained characteristics of MSCs, the latter showed less migratory characteristics and was not detected in other organs. CONCLUSION:Co-transplanting SSCs and TGFß1-treated MSCs significantly improves the recovery of endogenous SSCs and increases the homing efficiency of transplanted SSCs. This procedure could become an efficient method to treat infertility in a clinical setup, once the safety of the technique has been proven.

Project description:Bone marrow mesenchymal stem cells (BMSCs) are used as a great promising choice for the treatment of cerebral ischemia. Herein, we discuss the neuroprotective effects of the combination of BMSCs transplantation and mild hypothermia (MH) in an ischemia-reperfusion rat model. First, BMSCs were isolated using density gradient centrifugation and the adherent screening method, followed by culture, identification and labeling with DAPI. Second, adult male SD rats were divided into 5 groups: sham group (surgery without blockage of middle cerebral artery), model group (middle cerebral artery occlusion (MCAO) was established 2h prior to reperfusion), BMSCs group (injection of BMSCs via the lateral ventricle 24h after MCAO), MH group (mild hypothermia for 3h immediately after MCAO) and combination therapy group (combination of BMSCs and MH). Finally, the modified neurological severity score (mNSS) test was performed to assess behavioral function at different time points (before MCAO, before transplantation, at day 1, day 5 and day 10 after transplantation). After that, the brain was subjected to TTC staining, and the homing and angiogenesis were evaluated by immumofluorescence and immunohistochemistry. Immunofluorescence staining and Western Blot analysis were performed to calculate the percentage of the infarct area and explore glial fibrillary acidic protein (GFAP) and vascular endothelial growth factor (VEGF). Our results showed that the combination therapy significantly decreased mNSS scores (P<0.01) and reduced the percentage of the infarct area (P<0.01) than a single treatment. Moreover, the expression of GFAP and VEGF increased significantly in the combination therapy group (at day 5, day 10 after transplantation; at all time points after transplantation, respectively) compared to the single treatment groups. Taken together, it was suggested that the combination of BMSCs transplantation and MH can significantly reduce the percentage of the infarct area and improve functional recovery by promoting homing and angiogenesis, which may be a beneficial treatment for cerebral ischemia.

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Pioglitazone treatment prior to transplantation improves the efficacy of human mesenchymal stem cells after traumatic brain injury in rats.

Publications

Pioglitazone treatment prior to transplantation improves the efficacy of human mesenchymal stem cells after traumatic brain injury in rats.

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