Bone Marrow Mesenchymal Cell Transplantation Research Articles

Attenuation of Lipopolysaccharide-induced Liver Injury by Bone Marrow Mesenchymal Stem Cells via Inhibiting the NLRP3 Inflammasome and Hepatocyte Pyroptosis.

The transplantation of bone marrow mesenchymal cells (BMSCs) has been shown to be an effective mean for treating sepsis-related organ damage. Pytoptotic cell death, in turn, has recently been identified as a key driver of sepsis-related damage. At present, there are few studies on the effect of BMSC transplantation on pyroptotic cell death. We explored the ability of BMSCs to attenuate hepatic damage in a pyroptosis-related manner in a rat model of lipopolysaccharide (LPS)-induced liver injury. Following injury modeling and BMSC transplantation, we assessed the expression of the NLR family, pyrin domain containing 3 (NLRP3) inflammasome, and key downstream pyroptosis-related signaling molecules. It was found that BMSC transplantation was sufficient to significantly improve rat survival after LPS injection. A significantly reduced expression of the pyroptosis-related proteins NLRP3, caspase-1, IL-1β, and IL-18 in rats that had undergone BMSC transplantation compared to control animals was observed. Notably, this activity was superior to single-agent administration of the NLRP3 inhibitor MCC950. Our data suggest that BMSC transplantation may alleviate LPS-induced hepatic damage by suppressing the activation of the NLRP3 inflammasome and the induction of pyroptotic cell death.

Autologous Bone Marrow Mesenchymal Cell Transplantation in the Treatment of Freiberg's Disease: Case Report

Background: Osteonecrosis of the metatarsal head, classically known as Freiberg's disease, presents as aseptic necrosis of the epiphysis of undefined etiology, although it may be associated with trauma, prolonged corticotherapy or systemic diseases such as sickle cell disease. There are several techniques described for the treatment of osteonecrosis secondary to sickle cell disease. Methods: Case report and the surgical description of the use of autologous bone marrow mesenchymal stem cell transplantation for the treatment of osteonecrosis of the 2nd metatarsal head. Results: Nuclear magnetic resonance imaging performed after one year of follow-up showed a regression of the findings found in the preoperative evaluation. Conclusion: This is the first time that the technique of autologous bone marrow mesenchymal stem cell implantation has been employed for the treatment of osteonecrosis of the metatarsal head. The case reported shows that the technique is safe and brings good results after conservative treatment failure.

Efficacy and long-term longitudinal follow-up of bone marrow mesenchymal cell transplantation therapy in a diabetic patient with recurrent lower limb bullosis diabeticorum

Bullosis diabeticorum is a rare presentation of cutaneous manifestation most commonly affecting the lower limbs in patients with diabetes. The appearance, often as insidious as its resolution, is characterized by tense blisters on the skin surfaces of the lower limbs and the feet. The cause still remains unclear, but it may relate to microangiopathy and neuropathy. In this report, we present a case of a 64-year-old male with multiple episodes of blistering in the left lateral lower limb after a traumatic fall who was subsequently diagnosed with type 2 diabetes mellitus. The patient had a history of poorly controlled blood glucose and subsequently developed vasculopathy and peripheral neuropathy. Despite appropriate glycemic control and antibiotics therapy, the patient developed recurrent bullosis diabeticorum on five separate occasions during a 2-year span from 2005 to 2007. Building on our success with ischemic diabetic foot, we used bone marrow mesenchymal stem cell (BMMSC) transplantation therapy for bullosis diabeticorum. After a 9-month treatment, this patient developed another episode of cellulitis in the same lower limb which was successfully treated with antibacterial therapy. It is interesting that the patient reported no recurrence in the next 10-year follow-up span. This study demonstrates that bullosis diabeticorum could appear even before the onset of diabetes, and vascular insufficiency predisposes to the occurrence of bullosis diabeticorum. Our findings suggest that autologous BMMSC transplantation therapy may be an effective measure for recurrent bullosis diabeticorum; however, this will require further investigation to be conclusive. Early identification of diabetes and its complications and appropriate treatment may improve clinical outcomes and prevent lower limb amputation.Trial registration: ClinicalTrials.gov Identifier: NCT00955669. Registered on August 10, 2009.

Bone marrow mesenchymal cells improve muscle function in a skeletal muscle re-injury model.

Skeletal muscle injury is the most common problem in orthopedic and sports medicine, and severe injury leads to fibrosis and muscle dysfunction. Conventional treatment for successive muscle injury is currently controversial, although new therapies, like cell therapy, seem to be promise. We developed a model of successive injuries in rat to evaluate the therapeutic potential of bone marrow mesenchymal cells (BMMC) injected directly into the injured muscle. Functional and histological assays were performed 14 and 28 days after the injury protocol by isometric tension recording and picrosirius/Hematoxilin & Eosin staining, respectively. We also evaluated the presence and the fate of BMMC on treated muscles; and muscle fiber regeneration. BMMC treatment increased maximal skeletal muscle contraction 14 and 28 days after muscle injury compared to non-treated group (4.5 ± 1.7 vs 2.5 ± 0.98 N/cm2, p<0.05 and 8.4 ± 2.3 vs. 5.7 ± 1.3 N/cm2, p<0.05 respectively). Furthermore, BMMC treatment increased muscle fiber cross-sectional area and the presence of mature muscle fiber 28 days after muscle injury. However, there was no difference in collagen deposition between groups. Immunoassays for cytoskeleton markers of skeletal and smooth muscle cells revealed an apparent integration of the BMMC within the muscle. These data suggest that BMMC transplantation accelerates and improves muscle function recovery in our extensive muscle re-injury model.

Propofol promotes spinal cord injury repair by bone marrow mesenchymal stem cell transplantation.

Propofol is a neuroprotective anesthetic. Whether propofol can promote spinal cord injury repair by bone marrow mesenchymal stem cells remains poorly understood. We used rats to investigate spinal cord injury repair using bone marrow mesenchymal stem cell transplantation combined with propofol administration via the tail vein. Rat spinal cord injury was clearly alleviated; a large number of newborn non-myelinated and myelinated nerve fibers appeared in the spinal cord, the numbers of CM-Dil-labeled bone marrow mesenchymal stem cells and fluorogold-labeled nerve fibers were increased and hindlimb motor function of spinal cord-injured rats was markedly improved. These improvements were more prominent in rats subjected to bone marrow mesenchymal cell transplantation combined with propofol administration than in rats receiving monotherapy. These results indicate that propofol can enhance the therapeutic effects of bone marrow mesenchymal stem cell transplantation on spinal cord injury in rats.

Clinical safety and primary efficacy of bone marrow mesenchymal cell transplantation in subacute spinal cord injured patients

BackgroundIn recent years, some studies were conducted to evaluate the effects of stem cells from different sources on patients with spinal cord injury (SCI). This study was carried out to evaluate the feasibility and therapeutic potential of autologous bone marrow cell (BMC) transplantation in 11 complete spinal cord injured patients at thoracic level. Methods and materialsThis nonrandomized clinical trial compared the results of autologous BMC transplantation into cerebrospinal fluid (CSF) via lumbar puncture (LP) in 11 patients having complete SCI, with 20 patients as control group who received conventional treatment without BMC transplantation. The patients underwent preoperative and follow-up neurological assessments using the American Spinal Injury Association (ASIA) impairment scale. Then, the participants were followed for 12–33 months. ResultsEleven patients with the mean age of 33.2±8.9 years and 20 patients with the mean age of 33.5±7.2 years were enrolled in the study and in the control group, respectively. None of the patients in the study and control group experienced any adverse reaction and complications, neither after routine treatment nor after cell transplantation. Five patients out of 11 (45.5%) in the study group and three patients in the control group (15%) showed marked recovery, but the result was statistically borderline (P=0.095). ConclusionWe conclude that transplantation of autologous BMC via LP is a feasible and safe technique, but at the moment, no clear answer can be given regarding the clinical potential, despite a potential tendency to treat SCI patients, observed through statistics.

Bone marrow mesenchymal cell transplantation for heart diseases: mechanisms and applications

Current therapeutic strategies for the treatment of end-stage cardiac failure are limited. As the number of patients with refractory myocardial ischemia and congestive heart failure is rapidly rising there is urgent need for development of novel therapeutic approaches. Recent experimental studies based on innovative hypotheses utilizing cell therapy for damaged myocardium are promising. A number of cell types, including skeletal myoblasts, fetal cardiomyocytes, smooth muscle cells, embryonic stem cells and bone marrow mesenchymal cells (MSCs) have been tested for this purpose. Most evidence shows that MSCs might be one of the promising candidates as a therapeutic tool for the treatment of myocardial infarction and end-stage cardiac failure. Using a rat model with acute infarct heart generated by ligation of left anterior descending coronary artery, the mechanisms of transplanted MSCs on myocardial function recovery were investigated. The results confirmed that transplantation of MSCs improved cardiac function as assessed by measuring left ventricle ejection fraction and fraction of shortening based on Echocardiography. Several factors might contribute to this functional improvement. First, transplanted MSCs expressed the specific markers for cardiomyocytes and endothelial cells 14 days after transplantation, indicating that these cells gained new phenotypes. Second. Transplantation of MSCs upregulated endogenous VEGF and HO-1 expression in an early stage of heart infarction, thus enhanced angiogenesis and myocardial protection. Third, MSCs transplantation inhibited cardiomyocytes apoptosis by regulating the expressions of bcl-2 and bax. Fourth, MSC transplantation led to dynamic changes in the collagen network through regulation of MMP2/TIMP1 and consequently interrupted the progress of adverse left ventricle's remodeling. Fifth, some cytokines or growth factors either secreted by transplanted cells or endogenous cells might contribute to the improvement of damaged heart function.

Present status of and future direction for articular cartilage repair

Articular cartilage defects are a major clinical problem for orthopedic surgeons. About 10 years ago, autologous chondrocyte implantation (ACI) was explored [1], approved by the U.S. Food and Drug Administration (FDA), and performed in more than 20 000 patients worldwide. However, the effectiveness of ACI remains controversial because of the lack of evidence of effi cacy from randomized controlled trials. There is currently no satisfactory clinical technique that is widely accepted for the regenerative repair of these lesions. Current clinical practice usually involves a bone marrow stimulation technique, which involves subchondral bone breaking to facilitate cartilage repair from bone marrow-derived cells and cytokines. However, with this procedure, cartilage defects are repaired with fi brocartilage [2]. Almost 15 years ago, mosaicplasty [3,4] was explored in addition to ACI. Using this technique, we can repair small articular cartilage defects with hyaline cartilage, but there are still a number of problems that remain unsolved, such as donor site morbidity. In attempts to develop better methods, different cell sources and delivery vehicles, the addition of growth factors, and transduction of some genes have all been investigated. We have been interested in the use of bone marrow mesenchymal cells (BMMC) because they have a number of suitable properties [5–8]. First, it is easy to obtain autologous cells: this can be achieved by aspiration of blood from the bone marrow using local anesthesia, without major side effects. Another reason for our interest in using these cells is that because we can cause them to proliferate without their capacity for differentiation being lost, this technique can be applied in large articular cartilage defects. Therefore, this procedure can be performed clinically with relative ease. Thus, we performed BMMC transplantation in human articular cartilage defects in knee joints. In this article, we explain the articular cartilage repair procedure with cell transplantation, mainly focusing on those with BMMC transplantation.

Repair of articular cartilage defects in the patello-femoral joint with autologous bone marrow mesenchymal cell transplantation: three case reports involving nine defects in five knees

To investigate the effectiveness of autologous culture-expanded bone marrow mesenchymal cell transplantation for repairing articular cartilage defects, we transplanted autologous culture-expanded bone marrow mesenchymal cells into nine full-thickness articular cartilage defects of the patello-femoral joints (including two kissing lesions) in the knees of three patients, a 31 year-old female, a 44 year-old male and a 45 year-old male. Three weeks before transplantation, bone marrow blood was aspirated from the iliac crest. Adherent cells were cultured with media containing autologous serum. Single-passaged cells were collected, embedded in a collagen solution (5 x 10(6) cells/ml), placed on a collagen sheet, gelated, transplanted into the defect and covered with autologous periosteum or synovium. Six months after transplantation, the patients' clinical symptoms had improved and the improvements have been maintained over the follow-up periods (17-27 months). Histology of the first patient 12 months after the transplantation revealed that the defect had been repaired with the fibrocartilaginous tissue. Magnetic resonance imaging of the second patient 1 year after transplantation revealed complete coverage of the defect, but we were unable to determine whether or not the material that covered the defects was hyaline cartilage. Autologous bone marrow mesenchymal cells transplantation may be an effective approach to promote the repair of articular cartilage defects.

Increased heme oxygenase-1 expression in infarcted rat hearts following human bone marrow mesenchymal cell transplantation

Heme oxygenase-1 (HO-1) plays an important role in oxidative stress and recent studies indicate that it is a graft survival protein in cardiac and liver transplant models. In this study, we investigated the relation between the expressions of HO-1 and the effects of human bone marrow mesenchymal cells (MSCs) transplantation to xenogenic rat hearts with experimental myocardial infarction (MI). A total of 5 × 10 6 cells in 100 μl PBS or equal volume PBS alone were injected into the ischemic zones immediately post-MI. At 1, 3, and 7 days post-MI, cardiac function was evaluated by echocardiography, the expression of HO-1 was assessed by real-time PCR and Western blot, the localization of HO-1 protein was determined under immunofluorescence microscopy. The infarct size was examined by histology. The numbers of Hoechst-33342 positive MSCs were evaluated under immunofluorescence microscopy and also by flow cytometry after isolation from the host hearts. The results indicated that the HO-1 expressions were markedly increased at both mRNA and protein levels in comparison with injection of PBS at each time point post MSCs transplantation ( P < 0.01). HO-1 was revealed both in transplanted MSCs and recipient cardiomyocytes by immunofluorescence. Up-regulated HO-1 expression was accompanied by increase of the numbers of Hoechst-33342 positive MSCs, the reduction of infarct size, and the improvement of cardiac function. Transplantation of human MSCs could up-regulate HO-1 expression in infarct rat hearts, which might play an important role in protecting transplanted MSCs, cardiomyocytes survival, and cardiac function improvement during the early stage after MI.

Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees

Objective There is no widely accepted method to repair articular cartilage defects. Bone marrow mesenchymal cells have the potential to differentiate into bone, cartilage, fat and muscle. Bone marrow mesenchymal cell transplantation is easy to use clinically because cells can be easily obtained and can be multiplied without losing their capacity of differentiation. The objective of this study was to apply these cell transplantations to repair human articular cartilage defects in osteoarthritic knee joints.Design Twenty-four knees of 24 patients with knee osteoarthritis (OA) who underwent a high tibial osteotomy comprised the study group. Adherent cells in bone marrow aspirates were culture expanded, embedded in collagen gel, transplanted into the articular cartilage defect in the medial femoral condyle and covered with autologous periosteum at the time of 12 high tibial osteotomies. The other 12 subjects served as cell-free controls.Results In the cell-transplanted group, as early as 6.3 weeks after transplantation the defects were covered with white to pink soft tissue, in which metachromasia was partially observed. Forty-two weeks after transplantation, the defects were covered with white soft tissue, in which metachromasia was observed in almost all areas of the sampled tissue and hyaline cartilage-like tissue was partially observed. Although the clinical improvement was not significantly different, the arthroscopic and histological grading score was better in the cell-transplanted group than in the cell-free control group.Conclusions This procedure highlights the availability of autologous culture expanded bone marrow mesenchymal cell transplantation for the repair of articular cartilage defects in humans.

Repair of articular cartilage defect by cell transplantation

Full-thickness articular cartilage defects are a major clinical problem; however, at present there is no treatment that is widely accepted to regeneratively repair these lesions. The current therapeutic approach is to drill or abrade the base of the defect to expose the bone marrow with its cells and growth factors. This usually results in a repaired tissue of fibrocartilage that functions poorly in the loaded joint environment. Recently, autologous cultured chondrocyte transplantation and mosaic plasty were explored. We can repair small articular cartilage defects using these methods, although their effectiveness is still controversial. We have reported that transplantation of allogeneic chondrocytes embedded in collagen gels or allogeneic chondrocytes cultured in collagen gels could repair articular cartilage defect in a rabbit model. We also reported that autologous culture-expanded bone marrow mesenchymal cell transplantation could repair articular cartilage defect in a rabbit model. This procedure offers expedient clinical use, given that autologous bone marrow cells are easily obtained and can be culture-expanded. We transplanted autologous culture-expanded bone marrow cells into the cartilage defect of the osteoarthritic knee joint on 11 patients at the time of high tibial osteotomy. As early as 6.8 weeks after transplantation, the defect was covered with white soft tissue, in which slight metachromasia was histologically observed. Thirty-three weeks after transplantation, the repaired tissue had hardened. Histologically, repaired tissues showed stronger metachromasia and a partial hyaline cartilage-like appearance. This procedure may prove a promising method by which to repair articular cartilage defects.