Implantation Of Mesenchymal Stem Cells Research Articles

Bone marrow mesenchymal stem cell implantation for the treatment of radioactivity‑induced acute skin damage in rats.

The present study aimed to observe the role of mesenchymal stem cells (MSCs) in the repair of acute skin damage caused by radiation. Rat bone marrow MSCs (BMSCs) were isolated and cultured in vitro. A rat model of radiation‑induced acute skin damage was established by irradiation of the hind legs of Sprague-Dawley rats using a linear accelerator (45 Gy). After irradiation, rats were randomly divided into two groups: BMSC group and control group. Rats in the BMSC group were treated with a tail vein injection of 2x106 BMSCs (1 ml) immediately after irradiation and a local multipoint injection of 2x106 BMSCs at the injured area two weeks later. Then the wound healing of each rat was observed. The expression of transforming growth factor (TGF)‑β1, stromal cell‑derived factor-1 (SDF‑1) and prostaglandin E2 (PGE2) in the wounded tissues was determined by immunohistochemistry. The results demonstrated that skin damage was milder in the BMSC group than in the control group. Moreover, the speed of healing in the BMSC group was better than that in the control group. In addition, the wound score, it was significantly lower in the BMSC group than in the control group (P<0.05). The expression of PGE2 and TGF‑β1 in the BMSC group was also significantly lower than that in the control group (P<0.05), whereas the SDF‑1 expression was significantly higher in the BMSC group than that in the control group (P<0.05). BMSCs can effectively reduce inflammation and fibrosis in the wounded skin and promote the repair of acute radioactive skin injury. Thus, may be developed as a novel treatment for wound healing.

Efficacy of supraspinatus tendon repair using mesenchymal stem cells along with a collagen I scaffold.

ObjectivesOur main objective was to biologically improve rotator cuff healing in an elderly rat model using mesenchymal stem cells (MSCs) in combination with a collagen membrane and compared against other current techniques.MethodsA chronic rotator cuff tear injury model was developed by unilaterally detaching the supraspinatus (SP) tendons of Sprague-Dawley rats. At 1 month postinjury, the tears were repaired using one of the following techniques: (a) classical surgery using sutures (n = 12), (b) type I collagen membranes (n = 15), and (c) type I collagen membranes + 1 × 106 allogeneic MSCs (n = 14). Lesion restoration was evaluated at 1, 2, and 3 months postinjury based on biomechanical criteria. Continuous variables were described using mean and standard deviation (SD). To analyse the effect of the different surgical treatments in the repaired tendons’ biomechanical capabilities (maximum load, stiffness, and deformity), a two-way ANOVA model was used, introducing an interaction between such factor and time (1, 2, and 3 months postinjury).ResultsWith regard to maximum load, we observed an almost significant interaction between treatment and time (F = 2.62, df = 4, p = 0.053). When we analysed how this biomechanical capability changed with time for each treatment, we observed that repair with OrthADAPT and MSCs was associated with a significant increase in maximum load (p = 0.04) between months 1 and 3. On the other hand, when we compared the different treatments among themselves at different time points, we observed that the repair with OrthADAPT and MSCs has associated with a significant higher maximum load, when compared with the use of suture, but only at 3 months (p = 0.014). With regard to stiffness and deformity, no significant interaction was observed (F = 1.68, df = 4, p = 0.18; F = 0.40, df = 4, p = 0.81; respectively).ConclusionsThe implantation of MSCs along with a collagen I scaffold into surgically created tendon defects is safe and effective. MSCs improved the tendon’s maximum load over time, indicating that MSCs could help facilitate the dynamic process of tendon repair.

The role of “cell therapy” in osteonecrosis of the femoral head

Background and purpose — The value of core decrompression for treatment of osteonecrosis of the femoral head (ONFH) is unclear. We investigated by a literature review whether implantation of autologous bone marrow aspirate, containing high concentrations of pluripotent mesenchymal stem cells, into the core decompression track would improve the clinical and radiological results compared with the classical method of core decompression alone. The primary outcomes of interest were structural failure (collapse) of the femoral head and conversion to total hip replacement (THR).Patients and methods — All randomized and non-randomized control trials comparing simple core decompression with autologous bone marrow cell implantation into the femoral head for the treatment of ONFH were considered eligible for inclusion. The methodological quality of the studies included was assessed independently by 2 reviewers using the Cochrane Collaboration tool for assessing risk of bias in randomized studies. Of 496 relevant citations identified, 7 studies formed the basis of this review.Results — The pooled estimate of effect size for structural failure of the femoral head favored the cell therapy group, as, in this treatment group, the odds of progression of the femoral head to the collapse stage were reduced by a factor of 5 compared to the CD group (odds ratio (OR) = 0.2, 95% CI: 0.08–0.6; p = 0.02). The respective summarized estimate of effect size yielded halved odds for conversion to THR in the cell therapy group compared to CD group (OR = 0.6, 95% CI: 0.3–1.02; p = 0.06).Interpretation — Our findings suggest that implantation of autologous mesenchymal stem cells (MSCs) into the core decompression track, particularly when employed at early (pre-collapse) stages of ONFH, would improve the survivorship of femoral heads and reduce the need for hip arthroplasty.

Autologous mesenchymal stem cell implantation in the management of osteonecrosis of the femoral head

Autologous mesenchymal stem cell implantation in the management of osteonecrosis of the femoral head

Mesenchymal Stem Cell Implantation in Knee Osteoarthritis

Background: Several clinical studies have reported on cell-based treatment using mesenchymal stem cells (MSCs) for cartilage regeneration in knee osteoarthritis (OA). However, little is known about the factors that influence the clinical outcomes after surgery. Purpose/Hypothesis: This study aimed to investigate the clinical outcomes of MSC implantation in patients with knee OA and assess the factors that are associated with clinical outcomes. The hypothesis was that factors may exist that could influence clinical outcomes. Study Design: Case series; Level of evidence, 4. Methods: A total of 49 patients (55 knees) were retrospectively evaluated after MSC implantation for knee OA. The inclusion criteria were patients who had an isolated full-thickness cartilage lesion and Kellgren-Lawrence OA grade 1 or 2. Clinical outcomes were measured with the International Knee Documentation Committee (IKDC) score, Tegner activity score, and patients’ overall satisfaction with the surgery. Statistical analyses were performed to determine the effect of different factors on the clinical outcome. Results: The mean pre- and postoperative IKDC and Tegner activity scores significantly improved from 37.7 ± 6.3 to 67.3 ± 9.5 (IKDC) and from 2.2 ± 0.7 to 3.8 ± 0.7 (Tegner) (P < .001 for both). Twenty-four patients reported their overall satisfaction with the surgery as excellent (43.6%), 17 as good (30.9%), 11 as fair (20.0%), and 3 as poor (5.5%). There were significant differences in clinical outcomes at the final follow-up among the age and lesion size groups (P < .05 for all). Multivariate analyses showed high prognostic significance related to patient age and lesion size, and scatter plots suggested a cutoff age of 60 years and a cutoff lesion size of 6.0 cm2 for the optimum identification of poor clinical outcomes (P < .05 for both). Conclusion: The clinical outcomes of MSC implantation for knee OA are encouraging. Patient age and lesion size are important factors that affect clinical outcomes; thus, these may serve as a basis for preoperative surgical decisions. Cutoff points exist for the risk of clinical failure in patients older than 60 years and those with a lesion size larger than 6.0 cm2.

Examination of bone marrow mesenchymal stem cells seeded onto poly(3-hydroxybutyrate-co-4-hydroxybutyrate) biological materials for myocardial patch

The implantation of bone marrow mesenchymal stem cells (BMSCs) into the heart has been reported to be effective for myocardial infarction; however, it is unknown what methods are most suitable for supporting stem cell growth in a myocardial patch. This study used a new polymer material composed of poly(3-hydroxybutyrate-co-4-hydroxybutyrate) [P(3HB-co-4HB)] co-cultured with BMSCs to create a myocardial patch. Bone marrow mesenchymal stem cells were obtained from healthy male BSL-C57 mice. The cells were treated with 5-azacytidine to investigate their differentiation into cardiomyocytes. The cells were seeded for 24-hours onto P(3HB-co-4HB) biological material films (n = 8). Cell-biomaterial constructs were fixed and analyzed using different methods. Bone marrow mesenchymal stem cells were CD34, CD45− , CD90+ (low), and CD73+. The cells were stained with anti-cardiac troponin T (anti-cTnT) and anti-connexin 43 (anti-CX43) antibodies after 5-azacytidine treatment. Scanning electron microscopy showed that BMSC morphology was normal, and cell numbers were more abundant on the P(3HB-co-4HB) material surfaces. The growth curve of BMSCs on the biomaterial patches showed that the P(3HB-co-4HB) material permitted good stem cell growth. Owing to its excellent biocompatibility and biodegradability properties, in particular its porosity, P(3HB-co-4HB) is highlighted as an optimal material to support myocardial cell growth and myocardial patch formation in patients with myocardial infarction.

Expression of SDF-1/CXCR4 in acute infarct myocardium after implantation of bone marrow mesenchymal stem cells in rats

To explore the role of stromal cell derived factor-1 (SDF-1)/CXCR4 axis in acute infarct myocardium after an implantation of bone marrow mesenchymal stem cells (MSCs) in rats. The animals were anesthetized by an intraperitoneal injection of pentobarbital sodium. Left anterior thoracotomy through 3/4 intercostals region was performed and then left anterior descending coronary arteries were ligated for modeling acute myocardial infarction. The MSCs were injected into the area of acute infarct myocardium after a 10-minute ligation of left anterior descending coronary artery. The different concentration and expression of SDF-1/CXCR4 in the area of acute myocardial infarction and left ventricular function were analyzed. At day 28 post-transplantation, the vascular density in MSCs implant group were significantly higher than that in control group (P<0.05). And left ventricular function in MSCs implant group improved significantly than that in control group too (P<0.05). At the same time, the expressions of SDF-1 and CXCR4 in topical injection sites of infarct myocardium were significantly higher than those in control group (P<0.05). In MSCs implant group, the level of SDF-1/CXCR4 peaked at Day 1 post-transplantation and then it declined. After the implantation of MSCs into acute infarct myocardium, there is vascular regeneration and the level of SDF-1/CXCR4 increases so that left ventricular function improves. And the mechanism may be due to an up-regulation of SDF-1/CXCR4 axis.

Graphene oxide flakes as a cellular adhesive: prevention of reactive oxygen species mediated death of implanted cells for cardiac repair.

Mesenchymal stem cell (MSC) implantation has emerged as a potential therapy for myocardial infarction (MI). However, the poor survival of MSCs implanted to treat MI has significantly limited the therapeutic efficacy of this approach. This poor survival is primarily due to reactive oxygen species (ROS) generated in the ischemic myocardium after the restoration of blood flow. ROS primarily causes the death of implanted MSCs by inhibiting the adhesion of the MSCs to extracellular matrices at the lesion site (i.e., anoikis). In this study, we proposed the use of graphene oxide (GO) flakes to protect the implanted MSCs from ROS-mediated death and thereby improve the therapeutic efficacy of the MSCs. GO can adsorb extracellular matrix (ECM) proteins. The survival of MSCs, which had adhered to ECM protein-adsorbed GO flakes and were subsequently exposed to ROS in vitro or implanted into the ischemia-damaged and reperfused myocardium, significantly exceeded that of unmodified MSCs. Furthermore, the MSC engraftment improved by the adhesion of MSCs to GO flakes prior to implantation enhanced the paracrine secretion from the MSCs following MSC implantation, which in turn promoted cardiac tissue repair and cardiac function restoration. This study demonstrates that GO can effectively improve the engraftment and therapeutic efficacy of MSCs used to repair the injury of ROS-abundant ischemia and reperfusion by protecting implanted cells from anoikis.

Autologous mesenchymal stem cell implantation in the management of osteonecrosis of the femoral head

Autologous mesenchymal stem cell implantation in the management of osteonecrosis of the femoral head

Intrapericardial administration of mesenchymal stem cells in a large animal model: a bio-distribution analysis.

The appropriate administration route for cardiovascular cell therapy is essential to ensure the viability, proliferative potential, homing capacity and implantation of transferred cells. At the present, the intrapericardial administration of pharmacological agents is considered an efficient method for the treatment of cardiovascular diseases. However, only a few reports have addressed the question whether the intrapericardial delivery of Mesenchymal Stem Cells (MSCs) could be an optimal administration route. This work firstly aimed to analyze the pericardial fluid as a cell-delivery vehicle. Moreover, the in vivo biodistribution pattern of intrapericardially administered MSCs was evaluated in a clinically relevant large animal model. Our in vitro results firstly showed that, MSCs viability, proliferative behavior and phenotypic profile were unaffected by exposure to pericardial fluid. Secondly, in vivo cell tracking by magnetic resonance imaging, histological examination and Y-chromosome amplification clearly demonstrated the presence of MSCs in pericardium, ventricles (left and right) and atrium (left and right) when MSCs were administered into the pericardial space. In conclusion, here we demonstrate that pericardial fluid is a suitable vehicle for MSCs and intrapericardial route provides an optimal retention and implantation of MSCs.

Mesenchymal stem cells in the treatment of type 1 diabetes mellitus.

Diabetes mellitus type 1 is a form of diabetes mellitus that results from the autoimmune destruction of insulin-producing beta cells in the pancreas. The current gold standard therapy for pancreas transplantation has limitations because of the long list of waiting patients and the limited supply of donor pancreas. Mesenchymal stem cells (MSCs), a relatively new potential therapy in various fields, have already made their mark in the young field of regenerative medicine. Recent studies have shown that the implantation of MSCs decreases glucose levels through paracrine influences rather than through direct transdifferentiation into insulin-producing cells. Therefore, these cells may use pro-angiogenic and immunomodulatory effects to control diabetes following the cotransplantation with pancreatic islets. In this review, we present and discuss new approaches of using MSCs in the treatment of diabetes mellitus type 1.

Qualitative and quantitative analysis of MR imaging findings in patients with middle cerebral artery stroke implanted with mesenchymal stem cells.

Mesenchymal stem cells have potential as a regenerative therapy in ischemic stroke. We sought to determine MR imaging findings after mesenchymal stem cell implantation in chronic middle cerebral artery infarcts and to compare brain volume changes in patients with mesenchymal stem cells with those in age-matched healthy controls and controls with chronic stable MCA infarcts. We retrospectively identified 5 patients receiving surgical mesenchymal stem cell implantation to an MCA infarct from January 1, 2005, to July 1, 2013, with MR imaging immediately and 1 year postimplantation. Images at both time points were evaluated for any postimplantation complications. Structural image evaluation using normalization of atrophy software was used to determine volume changes between time points and compare them with those in healthy and age- and sex-matched controls with chronic, stable MCA infarcts by using Kruskal-Wallis and Mann-Whitney U tests. Susceptibility signal loss and enhancement at the implantation site were seen. No teratoma, tumor, or heterotopia was identified. Volumetric analysis showed a trend toward less overall volume loss after mesenchymal stem cell implantation (0.736; 95% CI, -4.15-5.62) compared with that in age- and sex-matched controls with chronic, stable MCA infarcts (-3.59; 95% CI, -12.3 to -5.21; P = .09), with a significantly greater growth-to-loss ratio in infarcted regions (1.30 and 0.78, respectively, P = .02). A trend toward correlation of growth-to-loss ratio with improvement in physical examination findings was seen (r = 0.856, P = .06). Postoperative changes consistent with stereotactic implantation were seen, but no teratoma, tumor, or heterotopia was identified. Initial findings suggest a trend toward less volume loss after mesenchymal stem cell implantation compared with that in age- and sex-matched controls with chronic, stable MCA infarcts, with a significantly greater growth-to-loss ratio in the infarcted tissue.

Mesenchymal stem cells modified with nerve growth factor improve recovery of the inferior alveolar nerve after mandibular distraction osteogenesis in rabbits

Distraction osteogenesis is widely used in the treatment of bony deformities and defects. However, injury to the inferior alveolar nerve is a concern. Our aim was to investigate the feasibility of using lentiviral-mediated human nerve growth factor beta (hNGFβ) of the inferior alveolar nerve in mandibular distraction osteogenesis in rabbits. To achieve this, mesenchymal stem cells (MSC) from the bone marrow of rabbit mandibles were isolated and genetically engineered using recombinant lentiviral vector containing hNGFβ. Twenty New Zealand white rabbits underwent mandibular distraction osteogenesis, and 5 million MSC transduced with hNGFβ-vector or control vector were transplanted around the nerve in the gap where the bone had been fractured during the operation (n=10 in each group). After gradual distraction, samples of the nerve were harvested for histological and histomorphometric analysis. We found that the genetically engineered MSC transduced by the lentiviral vector were able to secrete hNGFβ at physiologically relevant concentrations as measured by ELISA. Histological examination of the nerve showed more regenerating nerve fibres and less myelin debris in the group in which hNGFβ-modified MSC had been implanted than in the control group. Histomorphometric analysis of the nerve showed increased density of myelinated fibres in the group in which hNGFβ-modified MSC had been implanted than in the control group. The data suggest that implantation of hNGFβ-modified MSC can accelerate the morphological recovery of the inferior alveolar nerve during mandibular distraction osteogenesis in rabbits. The use of lentiviral-mediated gene treatment to deliver hNGFβ through MSC may be a promising way of minimising injury to the nerve.

Are CXCL13/CXCR5/FAK critical regulators of MSCs migration and differentiation?

Osteonecrosis of the femoral head is a common and challenging disease worldwide. The traditional treatments, such as core decompression procedure and joint replacement, are not satisfactory due to the limited outcome, repetitive surgery and cost. In recent years, autologous mesenchymal stem cells (MSCs) implantation into the femoral head has emerged as a promising method. The homing and differentiation of MSCs is determined by chemokines and their receptors, specific signals present in the micro-environment of the damaged tissue. CXCL13/CXCR5, highly expressed in the osteoblast and MSCs, are tissue specific and selectively migrate MSCs, thereafter triggering phosphorylation of focal adhesionkinase through mitogen-activated protein kinase pathway. Considering these characteristics, we hypothesize that CXCL13/CXCR5/FAK are critical signals in the trafficking and differentiation of MSCs.

Study of mesenchymal stem cells of adipose tissue effect on the growth of experimental glioma of the rats’ brain

Introduction. Relevant issue is the study of mesenchymal stem cells (MSC) effect on growth of tumors with different structures, including brain tumors. Materials and methods. The study was carried out on white rats. Stromal fraction of adult rats adipose tissue (AT) was prepared and cultured and subsequently administered to animals with glioma (strain 101.8). Results. Culturing cells of AT stromal-vascular adhesive fraction on day 10–12 we observed formation of fibroblast-like cells with MSC phenotype. Triple intraperitoneal injection of AT MSC on day 3, 5 and 8 after experimental glioma cell implantation did not significantly influenced animals longevity. At intracerebral implantation of tumor cells and AT MSC in a ratio 4:1 duration of disease clinical manifestations and illness in rats with glioma increased, that was accompanied by a tendency to mitotic activity reduce in tumor cells in areas between foci of necrosis. Conclusions. Intracerebral implantation of tumor cells and AT MSC causes prolong disease clinical manifestations and illness in rats with glioma.

Implantation of human umbilical cord mesenchymal stem cells for ischemic stroke: perspectives and challenges.

Ischemic stroke is a focal cerebral insult that often leads to many adverse neurological complications severely affecting the quality of life. The prevalence of stroke is increasing throughout the world, while the efficacy of current pharmacological therapies remains unclear. As a neuroregenerative therapy, the implantation of human umbilical cord mesenchymal stem cells (hUC-MSCs) has shown great possibility to restore function after stroke. This review article provides an update role of hUC-MSCs implantation in the treatment of ischemic stroke. With the unique "immunosuppressive and immunoprivilege" property, hUC-MSCs are advised to be an important candidate for allogeneic cell treatment. Nevertheless, most of the treatments are still at primary stage and not clinically feasible at the current time. Several uncertain problems, such as culture conditions, allograft rejection, and potential tumorigenicity, are the choke points in this cellular therapy. More preclinical researches and clinical studies are needed before hUC-MSCs implantation can be used as a routinely applied clinical therapy.

Intramuscular injection of bone marrow mesenchymal stem cells with small gap neurorrhaphy for peripheral nerve repair

We had previously reported that small gap neurorrhaphy by scissoring and sleeve-jointing epineurium could enhance the rate and quality of peripheral nerve regeneration. To date, local implantation and systemic delivery of bone marrow mesenchymal stem cells (BMSCs) have been routinely used in nerve tissue engineering, but they each have some intrinsic limitations. We hypothesised that targeted muscular administration of BMSCs capable of reaching the damaged nerve would be advisable. Here, we investigated the therapeutic efficacy of transplantation of BMSCs through targeted muscular injection with small gap neurorrhaphy by scissoring and sleeve-jointing epineurium on repairing peripheral nerve injury in a rat model. One week after a rat model of peripheral nerve injury was established by small gap neurorrhaphy, thirty-six Sprague–Dawley rats were randomly divided into three groups (n=12): the intramuscular injection of BMSCs group (IM), the intravenous injection of BMSCs group (IV) and the intramuscular injection of phosphate-buffered solution group (PBS). The process of the nerve regeneration was assayed functionally and morphologically. The results indicated that compared to the IV-treated and PBS-treated groups, the targeted muscular injection therapy resulted in much more beneficial effects, as evidenced by increases in the sciatic function index, nerve conduction velocity, myelin sheath thickness and restoration rate of gastrocnemius muscle wet weight. In conclusion, the combination therapy of small gap neurorrhaphy and BMSC transplantation through targeted muscular injection can significantly promote the regeneration of peripheral nerve and improve the nerve’s functional recovery, which may help establish a reliable approach for repairing peripheral nerve injury.

Abstract 17100: Priming with Erythropoietin Enhances Survival and Pro-Angiogenic Properties in Mesenchymal Stem Cells

Introduction: Accumulating evidence from animal studies shows that the administration of mesenchymal stem cells (MSCs) from bone marrow ameliorates tissue damage after ischemic injury. However, the inability to effectively graft culture-expanded stem cells to diseased or injured tissues remains a challenge for cell therapy. Erythropoietin (Epo) is an erythropoiesis-stimulating cytokine and protects erythroid progenitors from cell death. Epo receptor was identified in MSCs, but the action of Epo/Epo receptor signaling is not determined. In the present study we investigated whether Epo enhanced the survival and pro-angiogenic potential in the MCSs in both culture and animal experiments. Methods and Results: Epo receptor was expressed on MSCs isolated from bone marrow in GFP-transgenic rats. In culture study, the Epo treatment (80IU/ml) significantly propagated the MSCs compared with the controls (2-fold increase, p&lt;0.05). Quantitative RT-PCR analysis demonstrated that Epo significantly enhanced the expressions of basic-fibroblast growth factor and stromal cell-derived factor-1 in the cultured MSCs. In vivo, the GFP-MSCs preconditioned with and without Epo (80IU/ml) for 48 hours were locally administered to rat hindlimb ischemia model (n=11 in each group). Priming with Epo significantly increased the MSC engraftment in perivascular area of the injured muscle at day 3 after the implantation more than without Epo (1.5±1.3 vs. 3.0±2.1, p&lt;0.05). The MSCs preconditioned with Epo significantly promoted blood perfusion documented by laser Doppler and capillary growth in histological study compared with the control group at day 14 (p&lt;0.05, respectively). In addition to promoting neovascularization, the MSCs with Epo significantly inhibited macrophage infiltration in perivascular are (p&lt;0.05 vs. the control). Conclusions: Epo induced the proliferative activity and enhanced the production of angiogenic cytokines in the cultured MSCs from bone marrow. In vivo study demonstrated that the short-term priming with Epo promoted the cellular engraftment and neovascularization in the MSC therapy for ischemic limb muscle. MSC implantation combined with Epo may be a novel and feasible strategy in therapeutic angiogeneis.

Mesenchymal Stem Cell Implantation in Osteoarthritic Knees

Background: The cell-based tissue engineering approach that uses mesenchymal stem cells (MSCs) has addressed the issue of articular cartilage repair in osteoarthritic (OA) knees. However, to improve outcomes, an advanced surgical procedure with tissue-engineered scaffolds may be needed to treat patients with large cartilage lesions. Purpose: To investigate the clinical and second-look arthroscopic outcomes of the implantation of MSCs loaded in fibrin glue as a scaffold in patients with OA knees and to compare these outcomes with those of MSC implantation without a scaffold. Study Design: Cohort study; Level of evidence, 3. Methods: This study retrospectively evaluated 54 patients (56 knees) who were examined with second-look arthroscopy after MSC implantation for cartilage lesions in their OA knees. Patients were divided into 2 groups: 37 patients (39 knees) were treated with MSC implantation without a scaffold (group 1), and 17 patients (17 knees) underwent implantation of MSCs loaded in fibrin glue as a scaffold (group 2). Clinical outcomes were evaluated according to the International Knee Documentation Committee (IKDC) score and the Tegner activity scale, and cartilage repair was assessed with the International Cartilage Repair Society (ICRS) grade. Statistical analyses were performed to identify various prognostic factors associated with the clinical and second-look arthroscopic outcomes. Results: At final follow-up (mean, 28.6 months; range, 24-34 months), the mean IKDC score and Tegner activity scale in each group significantly improved: group 1, from 38.1 ± 7.7 to 62.0 ± 11.7 (IKDC) and from 2.5 ± 0.9 to 3.5 ± 0.8 (Tegner); group 2, from 36.1 ± 6.2 to 64.4 ± 11.5 (IKDC) and from 2.2 ± 0.8 to 3.8 ± 0.8 (Tegner) (P < .001 for all). According to the overall ICRS cartilage repair grades, 9 of the 39 lesions (23%) in group 1 and 12 of the 17 lesions (58%) in group 2 achieved a grade of I or II. There was a significant difference in ICRS grades between the groups (P = .028). Overweight (body mass index ≥ 27.5 kg/m2) and large lesion size (≥5.7 cm2) were significant predictors of poor clinical and arthroscopic outcomes in group 1 (P < .05 for both). There was a similar trend in group 2, but the differences were not significant, possibly owing to the smaller sample size. Conclusion: Clinical and arthroscopic outcomes of MSC implantation were encouraging for OA knees in both groups, although there were no significant differences in outcome scores between groups. However, at second-look arthroscopy, there were better ICRS grades in group 2.

MicroRNA-377 regulates mesenchymal stem cell-induced angiogenesis in ischemic hearts by targeting VEGF.

MicroRNAs have been appreciated in various cellular functions, including the regulation of angiogenesis. Mesenchymal-stem-cells (MSCs) transplanted to the MI heart improve cardiac function through paracrine-mediated angiogenesis. However, whether microRNAs regulate MSC induced angiogenesis remains to be clarified. Using microRNA microarray analysis, we identified a microRNA expression profile in hypoxia-treated MSCs and observed that among all dysregulated microRNAs, microRNA-377 was decreased the most significantly. We also validated that vascular endothelial growth factor (VEGF) is a target of microRNA-377 using dual-luciferase reporter assay and Western-blotting. Knockdown of endogenous microRNA-377 promoted tube formation in human umbilical vein endothelial cells. We then engineered rat MSCs with lentiviral vectors to either overexpress microRNA-377 (MSCmiR-377) or knockdown microRNA-377 (MSCAnti-377) to investigate whether microRNA-377 regulated MSC-induced myocardial angiogenesis, using MSCs infected with lentiviral empty vector to serve as controls (MSCNull). Four weeks after implantation of the microRNA-engineered MSCs into the infarcted rat hearts, the vessel density was significantly increased in MSCAnti-377-hearts, and this was accompanied by reduced fibrosis and improved myocardial function as compared to controls. Adverse effects were observed in MSCmiR-377-treated hearts, including reduced vessel density, impaired myocardial function, and increased fibrosis in comparison with MSCNull-group. These findings indicate that hypoxia-responsive microRNA-377 directly targets VEGF in MSCs, and knockdown of endogenous microRNA-377 promotes MSC-induced angiogenesis in the infarcted myocardium. Thus, microRNA-377 may serve as a novel therapeutic target for stem cell-based treatment of ischemic heart disease.