Bone Marrow Mesenchymal Stem Cells Transplantation Research Articles

Application of Bone Marrow Mesenchymal Stem Cells Effectively Eliminates Endotoxemia to Protect Rat from Acute Liver Failure Induced by Thioacetamide

Background:Endotoxemia is related to worse clinical outcomes in acute liver failure (ALF), but its management remains unsatisfactory. In this study, we aimed to assess whether the application of bone marrow mesenchymal stem cells (BMSCs) could eliminate endotoxemia and protect rats against ALF induced by thioacetamide (TAA).Methods:BMSCs were isolated from rats and identified by the specific morphology, differentiation potential, and surface markers. The optimal dose of TAA for this study was explored and TAA-induced ALF rats were randomized to three groups: the normal control group (Saline), ALF group (TAA + Saline), and BMSCs-treated group (TAA + BMSCs). The intestinal migration and differentiation of BMSCs was tracked in vivo, and intestinal permeability, endotoxin and inflammatory cytokines, histology, and mortality were analyzed. Moreover, we added the inhibitor of the PI3K/AKT/mTOR signaling pathway into the co-culture system of BMSCs with enterocytes and then performed CK and Villin expression experiments to assess the role of PI3K/AKT/mTOR signal pathway in the intestinal differentiation of BMSCs.Results:BMSCs migrated to the intestinal injury sites and differentiated into enterocytes, intestinal permeability was decreased compared with the ALF group. The higher expression of endotoxin and inflammatory cytokines were reversed after BMSCs transplantation in rats with ALF. Mortality and intestinal lesion were significantly decreased. Blocking the PI3K/AKT/mTOR signal pathway inhibited BMSCs’ intestinal differentiation in vitro.Conclusion:BMSCs can eliminate endotoxemia and reduce mortality in rats with ALF, and the PI3K/AKT/mTOR signal pathway is involved in intestinal differentiation. BMSCs transplantation could be a potential candidate for the treatment of endotoxemia in ALF.

Autologous Dedifferentiated Osteogenic Bone Marrow Mesenchymal Stem Cells Promote Bone Formation in a Rabbit Model of Anterior Cruciate Ligament Reconstruction versus Bone Marrow Mesenchymal Stem Cells

This study aimed to verify whether transplantation of dedifferentiated osteogenic bone marrow mesenchymal stem cells (De-BMSCs) at the tendon-bone interface could result in more bone formation than BMSC transplantation in anterior cruciate ligament (ACL) reconstruction. BMSCs from femur and tibia of New Zealand White rabbit were subjected to osteogenic induction and then cultured in osteogenic factor-free medium; the obtained cell population was termed De-BMSCs. Bilateral ACL reconstruction was performed in 48 adult rabbits. Three groups were established: control group with alginate gel injection, BMSCs group with the BMSCs injection, and De-BMSCs group with the De-BMSCs injection. At week 4 and 12 postoperatively, tendon-bone healing by histologic staining, micro-computed tomography examination, and biomechanical test were evaluated. The expression of α1 chain of type I collagen, osteocalcin, and osteopontin at the tendon-bone interface in the De-BMSCs group was greater than in the control or BMSCs group. The bone volume/total volume by micro-computed tomography scan was significantly greater in the De-BMSCs group than that in the control group (P= .013) or BMSCs group (P= .045) at 4 weeks, and greater than that in the control group (P= .014) or BMSCs group (P= .017) at 12 weeks. The tunnel area was significantly smaller in the De-BMSCs group than in the control group (P= .013) or BMSCs group (P= .044) at 12 weeks. The failure load and stiffness in De-BMSCs group were both significantly enhanced at 4 and 12 weeks than control group or De-BMSCs group. De-BMSCs transplantation can promote bone formation at the tendon-bone interface better than BMSCs transplantation in ACL reconstruction and increase the early biomechanical strength of the reconstructed ACL CLINICAL RELEVANCE: De-BMSCs transplantation is a potential choice for enhancing early bone formation in the tunnel in ACL reconstruction.

Role of Inflammatory Niche and Adult Cardiomyocyte Coculture on Differentiation, Matrix Synthesis, and Secretome Release by Human Bone Marrow Mesenchymal Stem Cells.

Myocardial infarction (MI) causes cardiomyocyte death, provokes innate immune response, and initiates tissue remodeling. The intrinsic healing process is insufficient to replace the lost cells, or regenerate and restore the functional features of the native myocardium. Autologous bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation is being explored to offer therapeutic potential after MI. Here, we cultured human BM-MSC spheroids in three-dimensional collagenous gels for 28days under exposure to tumor necrosis factor-alpha (+ TNFα), and coculture with adult human cardiomyocytes, or with conditioned media (CM) pooled from TNFα-stimulated adult cardiomyocytes. MSC differentiation marker (CD90, GATA4, cTnI, cTnT, Cx43, MHC, α-actin) expression, matrix protein (elastin, hyaluonic acid, sulfated glycosaminoglycans, laminin, fibrillin, nitric oxide synthase) synthesis, and secretome (cytokines, chemokines, growth factors) release at days 12 and 28 were assessed. MSC density decreased with duration in all culture conditions, except in controls. GATA4 expression was higher in cocultures but lower in + TNFα cultures. Synthesis and deposition of various extracellular matrix proteins and lysyl oxidase within MSC cultures, as well as secretome composition, were strongly dependent on the culture condition and duration. Results suggest that TNFα-induced inflammation suppresses BM-MSC survival and differentiation into mature cardiomyocytes by day 28, while promoting matrix protein synthesis and cytokine release conducive to MI remodeling. These findings could have implications in developing tissue engienering and cell transplantation strategies targeting MI, as well as to develop therapuetics to target inflammation-induced matrix remodeling post-MI.

Untargeted Metabolomics Reveal the Protective Effect of Bone Marrow Mesenchymal Stem Cell Transplantation Against Ovariectomy-Induced Osteoporosis in Mice

Bone marrow mesenchymal stem cell transplantation (BMSCT) is a potential treatment for osteoporosis, capable of contributing to bone tissue repair. BMSCT has demonstrated osteoinductive effects and the ability to regulate microenvironmental metabolism; however, its role and mechanisms in bone loss due to reduced estrogen levels remain unclear. In this study, the effect of BMSCT on ovariectomy (OVX)-induced osteoporosis in mice was assessed, and liquid chromatography–mass spectrometry (LC-MS) metabolomic studies of bone tissue were conducted to identify potential metabolic molecular markers. The results revealed that BMSCT reduces OVX-induced bone loss in mice while improving the mechanical properties of mouse femurs and increasing the expression of osteogenic markers in peripheral blood. In a metabolomic study, 18 metabolites were screened as potential biomarkers of the anti-osteoporotic effect of BMSCT. These metabolites are mainly involved in arachidonic acid metabolism, taurine and hypotaurine metabolism, and pentose and glucuronate interconversions. Collectively, these results illustrate the correlation between metabolites and the underlying mechanisms of osteoporosis development and are important for understanding the role and mechanisms of exogenous bone marrow mesenchymal stem cells (BMSCs) in osteoporosis management. This study lays the foundation for research on BMSCs as a treatment strategy for osteoporosis.

Effects of Foxc1 and Oct4 genes regulating BMSCs transplantation on cardiomyocyte apoptosis after acute myocardial infarction in rats

To investigate the effect of Foxc1 and Oct4 genes regulated by bone marrow mesenchymal stem cells (BMSCs) transplantation on cardiomyocyte apoptosis after acute myocardial infarction in rats. 180 healthy SD male rats were divided into 3 groups by random number table method, namely control group, acute myocardial infarction (AMI) group and BMSCs group. The rats were sacrificed 4 weeks after transplantation. The TUNEL method was used to detect the cardiomyocyte apoptosis index. The control group basically had no cardiomyocyte apoptosis, while the apoptosis indexes of AMI group (0.67 ± 0.14) was higher than that (0.31 ± 0.12) of BMSCs group (P < 0.05). The OD value of Foxc1 and Oct4 protein in BMSCs group was higher than those in AMI group (all P < 0.05). BMSCs transplantation can reduce cardiomyocyte apoptosis after AMI in rats. The mechanism may be related to the up-regulation of Oct4 and Foxc1 protein expression.

Transplantation of BMP-7 gene-transfected bone marrow mesenchymal stem cells for the treatment of spinal cord injury in rats

Background: Spinal cord injury (SCI) is a serious traumatic disease of the central nervous system, and there is currently no effective treatment for SCI because of its complicated pathophysiology. Bone marrow mesenchymal stem cells (BMSCs) have multidirectional differentiation abilities. Our study aims to explore the effects of bone morphogenetic protein 7 (BMP-7)-modified BMSCs transplantation on the repair of SCI in rats. Methods: In this study, a rat spinal cord injury model was established with the modified Allen method. Then, BMSCs transfected with the BMP7 gene were transplanted to treat the spinal cord injury in rats. Forty Sprague-Dawley rats were randomly divided into the sham operation group (sham group), spinal cord injury group (model group), BMSC treatment group (BMSC group) and LV-BMP7-BMSC treatment group (LV-BMP7-BMSC group). The Basso, Beattie, and Bresnahan (BBB) score was used to evaluate the recovery of hindlimb function in the rats. The levels of neurofilament protein NF-200 (NF-200) and glial fibrillary acidic protein (GFAP) were detected by immunofluorescence, RT-PCR and Western blotting. Results: At 14 d, 21 d, and 28 d after treatment, the BBB score of the rats in the LV-BMP7-BMSC group was higher than that of the rats in the model group and BMSC group. The results showed that NF-200 was expressed at the local spinal cord injury site. Compared with that of the sham group, the NF-200 expression level of the BMSC group and LV-BMP7-BMSC group was increased (P < 0.05). The results showed that the mRNA expression levels of NF-200 in the spinal cord tissue of the BMSC group and LV-BMP7-BMSC group were increased compared with those of the sham group (P < 0.05). The western blotting results further confirmed the PCR results. Conclusion: BMP-7 gene-modified BMSC transplantation can promote the repair of spinal cord functions after SCI in rats.

Effects and Mechanisms of Bone Marrow Mesenchymal Stem Cell Transplantation for Treatment of Ischemic Stroke in Hypertensive Rats.

Background and ObjectivesStroke is the most common cause of human death and functional disability, resulting in more than 5 million deaths worldwide each year. Bone marrow mesenchymal stem cells (BMSCs) are a kind of stem cell that are able to self-renew and differentiate into many types of tissues. Therefore, BMSCs have the potential to replace damaged neurons and promote the reconstruction of nerve conduction pathways and connective tissue. However, it remains unknown whether transplanted BMSCs promote angiogenesis or improve the tissue microenvironment directly or indirectly through paracrine interactions. This study aimed to determine the therapeutic effect of BMSCs on ischemic stroke with hypertension in a rodent model and to explore the possible mechanisms underlying any benefits.Methods and ResultsMiddle cerebral artery occlusion was used to establish the experimental stroke model. The area of cerebral infarction, expression of vascular endothelial growth factor (VEGF) and glial cell line-derived neurotrophic factor (GDNF), and increment of astrocyte were measured by TTC staining, western blot, real-time quantitative polymerase chain reaction (RT-qPCR) and immunocytochemistry. The results showed a smaller area of cerebral infarction and improved neurological function scores in animals treated with BMSCs compared to controls. The results of RT-qPCR and western blot assays showed higher expression of VEGF and GDNF in BMSC-treated animals compared with controls. Our study also showed that one round of BMSCs transplantation significantly promoted the proliferation of subventricular zone and cortical cells, especially astrocytes, on the ischemic side following cerebral ischemia.ConclusionsAbove findings support that BMSCs have therapeutic effects for ischemic stroke complicated with hypertension, which may occur via up-regulated expression of VEGF and GDNF and reduction of neuronal apoptosis, thereby promoting the recovery of nerve function.

Bone marrow mesenchymal stem cell therapy regulates gut microbiota to improve post-stroke neurological function recovery in rats

BACKGROUNDAs a cellular mode of therapy, bone marrow mesenchymal stem cells (BMSCs) are used to treat stroke. However, their mechanisms in stroke treatment have not been established. Recent evidence suggests that regulation of dysregulated gut flora after stroke affects stroke outcomes.AIMTo investigate the effects of BMSCs on gut microbiota after ischemic stroke.METHODSA total of 30 Sprague-Dawley rats were randomly divided into three groups, including sham operation control group, transient middle cerebral artery occlusion (MCAO) group, and MCAO with BMSC treatment group. The modified Neurological Severity Score (mNSS), beam walking test, and Morris water maze test were used to evaluate neurological function recovery after BMSC transplantation. Nissl staining was performed to elucidate on the pathology of nerve cells in the hippocampus. Feces from each group of rats were collected and analyzed by 16s rDNA sequencing.RESULTSBMSC transplantation significantly reduced mNSS (P < 0.01). Rats performed better in the beam walking test in the BMSC group than in the MCAO group (P < 0.01). The Morris water maze test revealed that the BMSC treatment group exhibited a significant improvement in learning and memory. Nissl staining for neuronal damage assessment after stroke showed that in the BMSC group, cells were orderly arranged with significantly reduced necrosis. Moreover, BMSCs regulated microbial structure composition. In rats treated with BMSCs, the abundance of potential short-chain fatty acid producing bacteria and Lactobacillus was increased.CONCLUSIONBMSC transplantation is a potential therapeutic option for ischemic stroke, and it promotes neurological functions by regulating gut microbiota dysbiosis.

Bone marrow-derived mesenchymal stem cells transplantation attenuates renal fibrosis following acute kidney injury by repairing the peritubular capillaries

After the severe initial insults of acute kidney injury, progressive kidney tubulointerstitial fibrosis may occur, the peritubular capillary (PTC) rarefaction plays a key role in the disease progression. However, the mechanisms of PTC damage were not fully understood and potential therapeutic interventions were not explored. Previous studies of our research team and others in this field suggested that bone marrow-derived mesenchymal stem cells (BMSCs) transplanted into the AKI rat model may preserve the kidney function and pathological changes. In the current study, with the ischemia/reperfusion AKI rat model, we revealed that BMSCs transplantation attenuated the renal function decrease in the AKI model through preserving the peritubular capillaries (PTCs) function. The density of PTCs is maintained by BMSCs transplantation in the AKI model, detachment and relocation of pericytes in the PTCs diminished. Then we established that BMSCs transplantation may attenuate the renal fibrosis and preserve the kidney function after AKI by repairing the PTCs. Improving the vitality of pericytes, suppressing the detachment and trans-differentiation of pericytes, directly differentiation of BMSCs into pericytes by BMSCs transplantation all participate in the PTC repair. Through these processes, BMSCs rescued the microvascular damage and improved the density of PTCs. As a result, a preliminary conclusion can be reached that BMSCs transplantation can be an effective therapy for delaying renal fibrosis after AKI.

Transplantation of IL-1β siRNA-modified bone marrow mesenchymal stem cells ameliorates type II collagen-induced rheumatoid arthritis in rats.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes erosion of articular cartilage and bone and has adverse effects on both patients and livestock animals. The aim of the present study was to investigate the role of interleukin-1β (IL-1β) in the pathogenesis of RA, and to further determine whether injection of IL-1β small interfering RNA (siRNA) or transplantation of IL-1β siRNA + bone marrow mesenchymal stem cells (BMSCs) can ameliorate RA in rats. A collagen-induced arthritis (CIA) rat model was established by injecting type II collagen for 4 weeks. Next, CIA rats were randomly divided into three groups and injected or transplanted with PBS, IL-1β siRNA and IL-1β siRNA + BMSCs for another 4 weeks. The CIA rat model was successfully established, as demonstrated by the higher toe swelling value, thymus and spleen/body weight, immobility time and serum IL-1β concentration, as well as lower body weight, climbing time and mRNA expression of programmed death-1 (PD-1), transforming growth factor-β1 (TGF-β1) and forkhead box protein 3 (Foxp3) in the spleen, compared with control rats. Furthermore, histopathology results demonstrated that joint swelling and redness were observed in the knee joints of CIA rats. H&E results revealed that CIA rats presented erosive destruction of the bone and ulceration of the articular cartilage. In addition, in vitro results demonstrated that IL-1β expression was successfully silenced after IL-1β siRNA transfection in lipopolysaccharide-stimulated BMSCs. When compared with the results of PBS rats, both IL-1β siRNA injection and IL-1β siRNA + BMSC transplantation significantly increased the body weight, climbing time and mRNA expression of PD-1, TGF-β1 and Foxp3 in the spleen, while significantly reduced the immobility time and serum IL-1β concentration. In addition, when compared with that of IL-1β siRNA injection, IL-1β siRNA + BMSC transplantation exhibited markedly higher therapeutic efficacy against CIA. These results demonstrated that higher IL-1β contributed to the pathogenesis of CIA, and that IL-1β siRNA injection ameliorated CIA, while its combination with BMSCs exerted synergistic effects, which may be beneficial against RA.

LINC00473-modified bone marrow mesenchymal stem cells incorporated thermosensitive PLGA hydrogel transplantation for steroid-induced osteonecrosis of femoral head: A detailed mechanistic study and validity evaluation.

The pathogenesis of steroid‐induced osteonecrosis of the femoral head (SONFH) involves a glucocorticoid‐induced imbalance of osteogenic and adipogenic differentiation, and apoptosis of bone marrow mesenchymal stem cells (BMSCs). An increasing number of genes, especially noncoding RNAs, have been implicated in the function of BMSCs. Our previous studies have confirmed the key role of LINC00473 and miR‐23a‐3p on the osteogenic, adipogenic differentiation, and apoptosis of BMSCs. However, the underlying mechanism of this process is still unclear. Based on bioinformatics analysis, here we investigated the effects of LINC00473 on the LRP5/Wnt/β‐catenin signaling pathway in the osteogenesis and adipogenesis of BMSCs, as well as the PEBP1/Akt/Bad/Bcl‐2 signaling pathway in dexamethasone‐ (Dex‐) induced apoptosis of BMSCs. Our data showed that LINC00473 could promote osteogenesis and suppress the adipogenesis of BMSCs through the activation of the miR‐23a‐3p/LRP5/Wnt/β‐catenin signaling pathway axis, while rescuing BMSCs from Dex‐induced apoptosis by activating the miR‐23a‐3p/PEBP1/Akt/Bad/Bcl‐2 signaling pathway axis. Notably, we observed that LINC00473 interacted with miR‐23a‐3p in an Argonaute 2 (AGO2)‐dependent manner based on dual‐luciferase reporter assay, AGO2‐related RNA immunoprecipitation, and RNA antisense purification assay. Furthermore, injectable thermosensitive polylactic‐co‐glycolic acid (PLGA) hydrogel loaded with rat‐derived BMSCs (rBMSCs) modified by LINC00473 were used for the treatment of SONFH in a rat model. Our results demonstrated that PLGA hydrogels provided a suitable environment for harboring rBMSCs. Besides, transplantation of PLGA hydrogels loaded with rBMSCs modified by LINC00473 could significantly promote the bone repair and reconstruction of the necrotic area at the femoral head in our SONFH rat model. Surprisingly, compared with the transplantation of BMSCs alone, the transplanted rBMSCs encapsulated within the PLGA hydrogel could migrate from the medullary cavity to the femoral head. In summary, LINC00473 promoted osteogenesis, inhibited adipogenesis, and antagonized Dex‐induced apoptosis of BMSCs. Therefore, LINC00473 could provide a new strategy for the treatment of SONFH.

Bone marrow derived-mesenchymal stem cell improves diabetes-associated fatty liver via mitochondria transformation in mice

BackgroundNon-alcoholic fatty liver disease (NAFLD) has become a global epidemic disease. Its incidence is associated with type 2 diabetes mellitus (T2DM). Presently, there is no approved pharmacological agents specially developed for NAFLD. One promising disease-modifying strategy is the transplantation of stem cells to promote metabolic regulation and repair of injury.MethodIn this study, a T2DM model was established through 28-week high-fat diet (HFD) feeding resulting in T2DM-associated NAFLD, followed by the injection of bone marrow mesenchymal stem cells (BMSCs). The morphology, function, and transfer of hepatocyte mitochondria were evaluated in both vivo and in vitro.ResultsBMSC implantation resulted in the considerable recovery of increasing weight, HFD-induced steatosis, liver function, and disordered glucose and lipid metabolism. The treatment with BMSC transplantation was accompanied by reduced fat accumulation. Moreover, mitochondrial transfer was observed in both vivo and vitro studies. And the mitochondria-recipient steatotic cells exhibited significantly enhanced OXPHOS activity, ATP production, and mitochondrial membrane potential, and reduced reactive oxygen species levels, which were not achieved by the blocking of mitochondrial transfer.ConclusionMitochondrial transfer from BMSCs is a feasible process to combat NAFLD via rescuing dysfunction mitochondria, and has a promising therapeutic effect on metabolism-related diseases.

Inhibition of the Notch1/Jagged1 pathway promotes homing of bone mesenchymal stem cells to improve asthma in rats

To explore the association of the Notch1/Jagged1 pathway with the homing of mesenchymal stem cells (BMSCs) to regulate Th1/Th2 drift in asthma. Twenty SD rats were randomly divided into normal control group, model group, BMSC transplantation group, and BMSC+Notch inhibitor group. Ovalbumin sensitization was used to establish rat models of asthma, and BMSCs were transplanted via the tail vein. The pathology of the lung tissue was examined with HE staining, and the contents of interleukin (IL)-5, IL-13, and interferon-γ (IFN-γ) in lung tissue homogenate were determined with enzyme-linked immunosorbent assay. The expressions of Notch1 and Jagged1 mRNA were detected with RT-PCR, and CXCR4 expression in the bronchial epithelial cells was examined using immunofluorescence staining; Western blotting was used to detect the protein expressions of T-bet, GATA-3, Notch1, and Jagged1 in the lung tissue. Compared with those in the control group, the expressions of IFN-γ and T-bet proteins decreased significantly and the pulmonary expressions of IL-5, IL-13, and GATA-3 proteins as well as Notch1 and Jagged1 mRNA and protein expressions all increased significantly in the model group (P < 0.05 or 0.01). Compared with those in the model group, CXCR4, IFN-γ, and T-bet protein expressions in BMSC group and BMSCs+Notch inhibitor group all increased significantly, and Notch1 and Jagged1 protein expressions in BMSCs group and IL-5, IL-13, Notch1, and Jagged1 mRNA and protein expressions in BMSCs + Notch inhibitor group all decreased significantly (P < 0.05 or 0.01). The expressions of CXCR4 and IFN-γ were significantly higher and the expressions of IL-13 and Notch1 mRNA were significantly lower in BMSCs+Notch inhibitor group than in BMSC group (P < 0.05). In asthmatic rats, the homing of the BMSCs to the lung tissue has a regulatory effect on Th1/Th2 drift, and the Notch1/Jagged1 pathway may participate in the homing of the BMSCs.

PARK7 promotes repair in early steroid-induced osteonecrosis of the femoral head by enhancing resistance to stress-induced apoptosis in bone marrow mesenchymal stem cells via regulation of the Nrf2 signaling pathway

Novel therapies for the treatment of early steroid-induced osteonecrosis of the femoral head (SONFH) are urgently needed in orthopedics. Transplantation of bone marrow mesenchymal stem cells (BMSCs) provides new strategies for treating this condition at the early stage. However, stress-induced apoptosis of BMSCs transplanted into the femoral head necrotic area limits the efficacy of BMSC transplantation. Inhibiting BMSC apoptosis is key to improving the efficacy of this procedure. In our previous studies, we confirmed that Parkinson disease protein 7 (PARK7) is active in antioxidant defense and can clear reactive oxygen species (ROS), protect the mitochondria, and impart resistance to stress-induced apoptosis in BMSCs. In this study, we investigated the mechanism driving this PARK7-mediated resistance to apoptosis in BMSCs. Our results indicate that PARK7 promoted the disintegration of nuclear factor (erythroid-derived 2)–like 2 (Nrf2)/Kelch-like echinacoside–associated protein 1 (Keap1) complex. The free Nrf2 then entered the nucleus and activated the genetic expression of manganese superoxide dismutase (MnSOD), catalase (CAT), glutathione peroxidase (GPx), and other antioxidant enzymes that clear excessive ROS, thereby protecting BMSCs from stress-induced apoptosis. To further explore whether PARK7-mediated resistance to stress-induced apoptosis could improve the efficacy of BMSC transplantation in early-stage SONFH, we transplanted BMSCs-overexpressing PARK7 into rats with early-stage SONFH. We then evaluated the survival of transplanted BMSCs and bone regeneration in the femoral head necrotic area of these rats. The results indicated that PARK7 promoted the survival of BMSCs in the osteonecrotic area and improved the transplantation efficacy of BMSCs on early-stage SONFH. This study provides new ideas and methods for resisting the stress-induced apoptosis of BMSCs and improving the transplantation effect of BMSCs on early-stage SONFH.

Irisin Enhances Angiogenesis of Mesenchymal Stem Cells to Promote Cardiac Function in Myocardial Infarction via PI3k/Akt Activation.

Background and ObjectivesWith the growing incidence of acute myocardial infarction (MI), angiogenesis is vital for cardiac function post-MI. The role of bone marrow mesenchymal stem cells (BMSCs) in angiogenesis has been previously confirmed. Irisin is considered a potential vector for angiogenesis. The objective of the present study was to investigate the potential role of irisin in the angiogenesis of BMSCs.Methods and ResultsIn vivo, irisin-treated BMSCs (BMSCs＋irisin) were transplanted into an MI mouse model. On day 28 post-MI, blood vessel markers were detected, and cardiac function and infarct areas of mice were evaluated. In vitro, paracrine effects were assessed by examining tube formation in human umbilical vein endothelial cells (HUVECs) co-cultured with the BMSCs＋irisin supernatant. The scratch wound-healing assay was performed to evaluate HUVEC migration. Western blotting was performed to determine PI3k/Akt pathway activation in the BMSCs＋irisin group. Transplantation of BMSCs＋irisin promoted greater angiogenesis, resulting in better cardiac function in the MI mouse model than in controls. In the BMSC＋irisin group, HUVECs demonstrated enhanced tube formation and migration. Activation of the PI3k/Akt pathway was found to be involved in mediating the role of irisin in the angiogenesis of BMSCs.ConclusionsIn cardiovascular diseases such as MI, irisin administration can enhance angiogenesis of BMSCs and promote cardiac function via the PI3k/Akt pathway, optimizing the therapeutic effect based on BMSCs transplantation.

Effect of bone marrow mesenchymal stem cell transplantation combined with lugua polypeptide injection on osteoarthritis in rabbit knee joint

ABSTRACT Purpose This study aimed to elucidate the effect of bone marrow mesenchymal stem cell (BMSC) transplantation combined with the administration of Lugua polypeptide injection into the knee joint cavity to treat knee osteoarthritis (KOA) in rabbits. Material and methods Sixty white New Zealand rabbits were randomly divided into the blank, model, Lugua polypeptide, BMSC, and combined (Lugua polypeptide plus BMSC) groups, with 12 rabbits in each group. The mRNA and protein expression levels of cyclin D1, bcl-2, TIMP-1, p21, caspase-3, Bax, MMP-1, MMP-13, TLR-4, and NF-κB p65 in chondrocytes, and levels of IL-1, NO, TNF-α, and IL-6 in the synovial fluid were compared. Results The severity of cartilage damage in the combined group was significantly less (P <0.01). Compared to the MG, the mRNA and protein expression levels of cyclin D1, bcl-2 and TIMP-1 in chondrocytes of the three other groups were significantly increased, while those of p21, caspase-3, Bax, MMP-1, MMP-13, TLR-4, and NF-κB p65 in the chondrocytes and levels of IL-1, NO, TNF-α, and IL-6 in the synovial fluid of the three other groups were significantly reduced (P <0.05). The aforementioned indicators in the combined group were significantly better than those of the Lugua polypeptide and BMSCs groups (P <0.05). Conclusions BMSC transplantation combined with Lugua polypeptide injection may improve KOA-related cartilage tissue damage in rabbits.

Effect of Warm Acupuncture Combined with Bone Marrow Mesenchymal Stem Cells Transplantation on Cartilage Tissue in Rabbit Knee Osteoarthritis

The current study was designed to investigate the effect and underlying mechanism of warm acupuncture combined with bone marrow mesenchymal stem cells (BMSC) transplantation on cartilage tissue injury in rabbit knee osteoarthritis (KOA). In the study, 50 rabbits were randomly divided into 5 groups: blank group, KOA group, warm acupuncture group, BMSCs group, and warm acupuncture combined with BMSCs group. After warm acupuncture combined with BMSCs, the Modified Lequesne MG knee joint assessment scale was used to evaluate the degree of knee joint behavior, the Taiping Peng method generally observed the histomorphology changes of KOA rabbit cartilage, and hematoxylin-eosin staining, safranin O green staining, and toluidine blue staining were conducted to evaluate the extent of cartilage tissue pathology. Furthermore, transmission electron microscopy and TUNEL staining were used to observe cell apoptosis, and immunohistochemistry and qPCR analysis were used to detect the expression of apoptosis-related proteins and mRNA. Results showed that administration of warm acupuncture combined with BMSCs recovered the joint function and significantly decreased Lequesne MG score. The degree of cartilage tissue pathological damage has been improved, cartilage ultrastructure degeneration has recovered, peripheral blood vessels have mild edema, blood supply has gradually recovered, and even small amounts of red blood cells have appeared. In addition, warm acupuncture combined with BMSCs treatment suppressed chondrocyte apoptosis in rabbits with knee osteoarthritis by reduced TUNEL-positive chondrocytes and simultaneously reversed the mRNA expression of Bax, Bcl-2, and Caspase-3. These results indicate that warm acupuncture combined with BMSCs transplantation has a potential protective effect on rabbit KOA, which may be mediated by inhibiting chondrocyte apoptosis.

Bone marrow-derived mesenchymal stem cells transplantation ameliorates renal injury through anti-fibrotic and anti-inflammatory effects in chronic experimental renovascular disease

BackgroundProgressive renal fibrosis is an underlying pathological process of chronic kidney disease (CKD) evolution. This study aimed to evaluate the roles of bone-marrow-derived mesenchymal stem cells (MSC) in the remodeling of fibrotic kidney parenchyma in the two kidneys-one clip (2K1C) CKD animal model. MethodsWistar rats were allocated into three groups: Sham, 2K1C, and 2K1C þ MSC. MSCs (106) were transplanted into the renal subcapsular region two weeks after clipping the left renal artery. Six weeks after clipping, left kidney samples were analyzed using histological and western blotting techniques. ANOVA tests were performed and differences between groups were considered statistically significant if p < 0.05. ResultsClipped kidneys of 2K1C rats displayed renal fibrosis, with excessive collagen deposition, glomerulosclerosis and renal basement membrane disruption. Clipped kidneys of 2K1C þ MSC rats showed preserved Bowman's capsule and tubular basement membranes, medullary tubules morphological reconstitution and reduced collagen deposits. Expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 were elevated, whereas tissue inhibitor of MMPs (TIMP)-1 and TIMP-2 levels were decreased in clipped kidneys of 2K1C rats. MSCs transplantation restored these expression levels. Moreover, MSCs suppressed macrophages and myofibroblasts accumulation, as well as TNF-a expression in clipped kidneys of 2K1C animals. MSCs transplantation significantly increased IL-10 expression. ConclusionsTransplanted MSCs orchestrate anti-fibrotic and anti-inflammatory events, which reverse renal fibrosis and promote renal morphological restoration. This study supports the notion that only one MSCs delivery into the renal subcapsular region represents a possible therapeutic strategy against renal fibrosis for CKD treatment.

Effects of bone marrow mesenchymal stem cells on repair and receptivity of damaged endometrium in rats.

This study was to investigate whether bone marrow mesenchymal stem cells (BMSCs) can repair damaged endometrium in rats and its effect on endometrial receptivity. A rat model of endometrial damage was established by heat injury. BMSCs were labeled with PKH26 and were transplanted into the right uterine cavity. The endometrial thickness and fertility testing were examined to assess the repair of damaged endometrium. The mass on trichrome staining was used to assess the endometrium fibrosis. The expression of integrin avβ3 and leukemia inhibitory factor (LIF) in rat endometrium was used to evaluate the endometrial receptivity. After transplantation of BMSCs, the distribution of PKH26 positive cells was mainly on the damaged side in the endometrial tissues. Compared to control group, the endometrial tissue structure recovered after treatment with BMSCs. BMSCs transplantation improved the fertility of endometrial injury model rats. BMSCs decreased the area of endometrial fibrosis. The expression of integrin avβ3 and LIF in endometrium was the stronger in BMSCs treatment group than control group. BMSCs can migrate to the endometrium and repair damaged endometrium and improve endometrium receptivity.

Targeting of Deciduous Tooth Pulp Stem Cell-Derived Extracellular Vesicles on Telomerase-Mediated Stem Cell Niche and Immune Regulation in Systemic Lupus Erythematosus.

Systemic transplantation of stem cells from human exfoliated deciduous teeth (SHED) is used to treat systemic lupus erythematosus (SLE)-like disorders in MRL/lpr mice. However, the mechanisms underlying the SHED-based therapy remain unclear. In this study, we hypothesized that trophic factors within SHED-releasing extracellular vesicles (SHED-EVs) ameliorate the SLE-like phenotypes in MRL/lpr mice. SHED-EVs were isolated from the culture supernatant of SHED. SHED-EVs were treated with or without RNase and systemically administered to MRL/lpr mice. Subsequently, recipient bone marrow mesenchymal stem cells (BMMSCs) isolated from SHED-EV-administered MRL/lpr mice were examined for the in vitro and in vivo activity of hematopoietic niche formation and immunoregulation. Furthermore, the recipient BMMSCs were secondarily transplanted into MRL/lpr mice. The systemic SHED-EV infusion ameliorated the SLE-like phenotypes in MRL/lpr mice and improved the functions of recipient BMMSCs by rescuing Tert mRNA-associated telomerase activity, hematopoietic niche formation, and immunoregulation. The secondary transplantation of recipient BMMSCs recovered the immune condition and renal functions of MRL/lpr mice. The RNase treatment depleted RNAs, such as microRNAs, within SHED-EVs, and the RNA-depleted SHED-EVs attenuated the benefits of SHED-EVs in MRL/lpr mice. Collectively, our findings suggest that SHED-secreted RNAs, such as microRNAs, play a crucial role in treating SLE by targeting the telomerase activity of recipient BMMSCs.