Marrow-derived Stem Cell Therapy Research Articles

Bone Marrow Mesenchymal Stem Cell with Up-Regulation of MicroRNA-206 in the Treatment of Bronchopulmonary Dysplasia in Newborn Mice

Background:: Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm neonates with a few therapeutic options. Our previous studies suggested that bone marrow-derived mesenchymal stem cell (BMSC) therapy is effective in the treatment of BPD in mouse models. Furthermore, microRNA-206 (miR-206) suggested having a correlation with BPD by regulating the expression of fibronectin 1 (FN1). Objectives:: The aim of this study was to characterize the role of BMSCs with the up-regulation of miR-206 in the treatment of BPD in newborn mice. Methods: The BPD mouse model was induced by 60% oxygen. BMSCs transfected with miR-206 or negative control (NC) plasmid were administered on postnatal day 7 (P7) and every following week through an intraperitoneal injection (105 cells/animal) until P35. The mice were weighed and their lungs were weighed and prepared for histology. The expression levels of miR-206, FN1, and pulmonary surfactant-associated protein-C (SP-C) were determined through the quantitative polymerase chain reaction and under the immunofluorescence. The protein expression levels of transforming growth factor-β1 (TGF-β1) and interleukin-6 (IL-6) were determined by ELISA. Results: BMSCs with up-regulation of miR-206 reduced the degrees of pulmonary edema, improved pulmonary architecture, and attenuated inflammation in BPD mice compared to the NC plasmid group. Furthermore, the up-regulation of miR-206 in BMSCs down-regulated the expression levels of TGF-β and IL-6 in plasma samples and of SP-C and FN1 in the lung tissue of BPD mice. Conclusions: BMSCs with up-regulation of miR-206 are effective in the treatment of BPD in newborn mice, and the study introduced a novel idea for the treatment of BPD.

Bone Marrow-Derived and Adipose-Derived Mesenchymal Stem Cell Therapy in Primary Knee Osteoarthritis: A Narrative Review.

Regenerative medicine in the context of musculoskeletal injury is a broad term that offers potential therapeutic solutions to restore or repair damaged tissue. The current focus in recent literature and clinical practice has been on cell based therapy. In particular, much attention has been centered on autologous bone marrow concentrate and adipose-derived mesenchymal stem cells (MSCs) for cartilage and tendon disorders. This article provides an overview of MSC-derived therapy and offers a comprehensive review of adipose- and bone marrow-derived MSC therapy in primary knee osteoarthritis. LEVEL OF EVIDENCE: IV.

3040 - Five Year Follow Up of Chronic Spinal Cord Injury Patients Receiving Autologous Bone Marrow-Derived Mesenchymal Stem Cell Therapy Combined with Physical Therapy

3040 - Five Year Follow Up of Chronic Spinal Cord Injury Patients Receiving Autologous Bone Marrow-Derived Mesenchymal Stem Cell Therapy Combined with Physical Therapy

Role of Autologous Bone Marrow-Derived Stem Cell Therapy for Follicular Recruitment in Premature Ovarian Insufficiency: Review of Literature and a Case Report of World's First Baby with Ovarian Autologous Stem Cell Therapy in a Perimenopausal Woman of Age 45 Year.

Stem cell (SC) therapy has come up enormously, particularly for indications where not much can be done medically or surgically to improve the condition. SCs are the foundation cells for every organ, tissue, and cell in the body, and it can either reproduce into a SC or differentiate into specialized types of cells. Premature ovarian insufficiency (POI) is a clinical syndrome defined by loss of ovarian activity before the age of 40 years. POI is characterized by menstrual disturbance (amenorrhea or oligomenorrhea) with raised gonadotropins, low anti-Mullerian hormone (AMH), and estradiol level. Autologous SCs were tried in POI to increase the follicular recruitment and avoiding the need for oocyte donation program. This review analyzes the causes, etiopathogenesis, and role of autologous bone marrow-derived SC therapy (ABMDSCT) in POI. It also highlights the recent studies and summarizes the current understanding and future directions for SCs in POI. Here, we also report the first successful birth of a baby from India, where autologous SC therapy in a 45-year-old perimenopausal single woman helped in procuring a pregnancy and delivery of a healthy 2.7 kg female baby through assisted reproduction. In the absence of SC therapy, accepting oocyte donor program or adoption would have been the only viable options for this patient for which she was not ready. This may be the world's first successful case of application of ABMDSCT in a 45-year-old female to give successful birth to a healthy baby.

Mesenchymal stem cell therapy for retro-corneal membrane - A clinical challenge in full-thickness transplantation of biosynthetic corneal equivalents.

The manuscript addresses the potential value of bone marrow-derived mesenchymal stem cell therapy for retro-corneal membrane (RCM) formation in full-thickness transplantation of biosynthetic corneal equivalents. This work reports the pathophysiological changes in the anterior chamber of the mouse eye following full-thickness recombinant human cross-linked collagen-based hydrogel implants in which persistent fibrin promotes the development of dense RCM. Furthermore, pre-treatment with mesenchymal stem cells reduces RCM formation and enhances corneal transparency.

Autologous bone marrow derived stem cell therapy in patients with type 2 diabetes mellitus - defining adequate administration methods.

AIMTo carry out randomized trial for evaluating effects of autologous bone marrow derived stem cell therapy (ABMSCT) through different routes.METHODSBone marrow aspirate was taken from the iliac crest of patients. Bone marrow mononuclear cells were separated and purified using centrifugation. These cells were then infused in a total of 21 patients comprising three groups of 7 patients each. Cells were infused into the superior pancreaticoduodenal artery (Group I), splenic artery (Group II) and through the peripheral intravenous route (Group III). Another group of 7 patients acted as controls and a sham procedure was carried out on them (Group IV). The cells were labelled with the PET tracer F18-FDG to see their homing and in vivo distribution. Data for clinical outcome was expressed as mean ± SE. All other data was expressed as mean ± SD. Baseline and post treatment data was compared at the end of six months, using paired t-test. Cases and controls data were analyzed using independent t-test. A probability (P) value of < 0.05 was regarded as statistically significant. Measures of clinical outcome were taken as the change or improvement in the following parameters: (1) C-peptide assay; (2) HOMA-IR and HOMA-B; (3) reduction in Insulin dose; subjects who showed reduction of insulin requirement of more than 50% from baseline requirement were regarded as responders; and (4) reduction in HbA1c.RESULTSAll the patients, after being advised for healthy lifestyle changes, were evaluated at periodical intervals and at the end of 6 mo. The changes in body weight, body mass index, waist circumference and percentage of body fat in all groups were not significantly different at the end of this period. The results of intra-group comparison before and after ABMSCT at the end of six months duration was as follows: (1) the area under C-peptide response curve was increased at the end of 6 mo however the difference remained statistically non-significant (P values for fasting C-peptide were 0.973, 0.103, 0.263 and 0.287 respectively and the P values for stimulated C-peptide were 0.989, 0.395, 0.325 and 0.408 respectively for groups I to IV); (2) the Insulin sensitivity indices of HOMA IR and HOMA B also did not show any significant differences (P values for HOMA IR were 0.368, 0.223, 0.918 and 0.895 respectively and P values for HOMA B were 0.183, 0.664, 0.206 and 0.618 respectively for groups I to IV); (3) Group Ishowed a significant reduction in Insulin dose requirement (P < 0.01). Group II patients also achieved a significant reduction in Insulin dosages (P = 0.01). The Group I and Group II patients together constituted the targeted group wherein the feeding arteries to pancreas were used for infusing stem cells. Group III, which was the intravenous group, showed a non-significant reduction in Insulin dose requirement (P = 0.137). Group IV patients which comprised the control arm also showed a significant reduction in Insulin dosages at the end of six months (P < 0.05); and (4) there was a non-significant change in the Hb A1c levels at the end of 6 mo across all groups (P = 0.355, P = 0.351, P = 0.999 and P = 0.408 respectively for groups I to IV).CONCLUSIONTargeted route showed a significant reduction in Insulin requirement at the end of six months of study period whereas the intravenous group failed to show reduction.

Phase I/II randomized controlled trial of autologous bone marrow-derived mesenchymal stem cell therapy for chronic stroke.

AIMTo examine the safety and efficacy of mesenchymal stem cell (MSC) therapy for intracerebral haemorrhage with neurological dysfunctions for a year.METHODSMSC were ex vivo expanded from 29 mL (17-42 mL) autologous bone marrow. Patients were randomized to have two intravenous injections of autologous MSC or placebos in four weeks apart. Neurological functions and clinical outcomes were monitored before treatment and at 12th, 16th, 24th, 36th and 60th week upon completion of the treatment.RESULTSA mean of 4.57 × 107 (range: 1.43 × 107-8.40 × 107) MSC per infusion was administered accounting to 8.54 × 105 (2.65 × 105-1.45 × 106) per kilogram body weight in two occasions. There was neither adverse event at time of administration nor sign of de novo tumour development among patients after monitoring for a year post MSC therapy. Neuro-restoration and clinical improvement in terms of modified Barthel index, functional independence measure and extended Glasgow Outcome Scale were evident among patients having MSC therapy compared to patients receiving placebos.CONCLUSIONIntravenous administration of autologous bone marrow-derived MSC is safe and has the potential of improving neurological functions in chronic stroke patients with severe disability.

A systematic review of randomised controlled trials examining the therapeutic effects of adult bone marrow-derived stem cells for non-ischaemic dilated cardiomyopathy.

BackgroundCertain early-phase clinical trials have suggested that bone marrow-derived stem cell transplantation might improve left ventricular function in patients with non-ischaemic dilated cardiomyopathy (NIDCM), whereas others trials have revealed no benefit from this approach. We sought to evaluate the therapeutic effects of bone marrow-derived stem cell therapy on NIDCM.MethodsWe searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases (through February 2016) for randomised controlled clinical trials that reported on bone marrow-derived stem cell transplantation for patients with NIDCM with a follow-up period ≥12 months. The co-primary endpoints were changes in mortality rate and left ventricular ejection fraction (LVEF); the secondary endpoints were changes in the 6-minute-walk test (6MWT) and left ventricular chamber size. Seven trials involving bone marrow-derived stem cell therapy that included 482 patients satisfied the inclusion and exclusion criteria.ResultsSubjects who received bone marrow-derived stem cell therapy exhibited a significant reduction in mortality rate (19.7% in the cell group vs. 27.1% in the control group; 95% confidence interval (CI) –0.16 to –0.00, I 2 = 52%, p = 0.04). Bone marrow-derived stem cell therapy tended to produce LVEF improvement within 6 months (1.83% increase; 95% CI –0.27 to 3.94, I 2 = 74%, p = 0.09) and significantly improved LVEF after mid-term (6–12 months) follow-up (3.53% increase; 95% CI 0.76 to 6.29, I 2 = 88%, p = 0.01). However, this therapy produced no significant benefit in the 6MWT (p = 0.18). Finally, the transplantation of increased numbers of stem cells resulted in no observable additional benefit with respect to LVEF.ConclusionsBone marrow-derived stem cell therapy might have improved prognoses and appeared to provide moderate benefits in cardiac systolic function at mid-term follow-up. However, this therapy produced no observed improvement in exercise tolerance.

Improving stem cell therapy in cardiovascular diseases: the potential role of microRNA.

The initial promising prospect of autologous bone marrow-derived stem cell therapy in the setting of cardiovascular diseases has been overshadowed by functional shortcomings of the stem cell product. As powerful epigenetic regulators of (stem) cell function, microRNAs are valuable targets for novel therapeutic strategies. Indeed, modulation of specific miRNA expression could contribute to improved therapeutic efficacy of stem cell therapy. First, this review elaborates on the functional relevance of miRNA dysregulation in bone marrow-derived progenitor cells in different cardiovascular diseases. Next, we provide a comprehensive overview of the current evidence on the effect of specific miRNA modulation in several types of progenitor cells on cardiac and/or vascular regeneration. By elaborating on the cardioprotective regulation of progenitor cells on cardiac miRNAs, more insight in the underlying mechanisms of stem cell therapy is provided. Finally, some considerations are made regarding the potential of circulating miRNAs as regulators of the miRNA signature of progenitor cells in cardiovascular diseases.

Assessment of bone marrow-derived Cellular Therapy in progressive Multiple Sclerosis (ACTiMuS): study protocol for a randomised controlled trial.

BackgroundWe have recently completed an evaluation of the safety and feasibility of intravenous delivery of autologous bone marrow in patients with progressive multiple sclerosis (MS). The possibility of repair was suggested by improvement in the neurophysiological secondary outcome measure seen in all participants. The current study will examine the efficacy of intravenous delivery of autologous marrow in progressive MS. Laboratory studies performed in parallel with the clinical trial will further investigate the biology of bone marrow-derived stem cell infusion in MS, including mechanisms underlying repair.Methods/designA prospective, randomised, double-blind, placebo-controlled, stepped wedge design will be employed at a single centre (Bristol, UK). Eighty patients with progressive MS will be recruited; 60 will have secondary progressive disease (SPMS) but a subset (n = 20) will have primary progressive disease (PPMS). Participants will be randomised to either early or late (1 year) intravenous infusion of autologous, unfractionated bone marrow. The placebo intervention is infusion of autologous blood. The primary outcome measure is global evoked potential derived from multimodal evoked potentials. Secondary outcome measures include adverse event reporting, clinical (EDSS and MSFC) and self-assessment (MSIS-29) rating scales, optical coherence tomography (OCT) as well as brain and spine MRI. Participants will be followed up for a further year following the final intervention. Outcomes will be analysed on an intention-to-treat basis.DiscussionAssessment of bone marrow-derived Cellular Therapy in progressive Multiple Sclerosis (ACTiMuS) is the first randomised, placebo-controlled trial of non-myeloablative autologous bone marrow-derived stem cell therapy in MS. It will determine whether bone marrow cell therapy can, as was suggested by the phase I safety study, improve conduction in multiple central nervous system pathways affected in progressive MS. Furthermore, laboratory studies performed in parallel with the clinical trial will inform our understanding of the cellular pharmacodynamics of bone marrow infusion in MS patients and the mechanisms underlying cell therapy.Trial RegistrationISRCTN27232902 Registration date 11/09/2012. NCT01815632 Registration date 19/03/2013

Nicorandil enhances the efficacy of mesenchymal stem cell therapy in isoproterenol-induced heart failure in rats

Stem cell transplantation has emerged as a promising technique for regenerative medicine in cardiovascular therapeutics. However, the results have been less than optimal. The aim of the present study was to investigate whether nicorandil could offer an additional benefit over bone marrow-derived mesenchymal stem cell therapy in isoproterenol-induced myocardial damage and its progression to heart failure in rats. Isoproterenol was injected subcutaneously for 2 consecutive days at doses of 85 and 170mg/kg/day, respectively. Nicorandil (3mg/kg/day) was then given orally with or without a single intravenous bone marrow-derived mesenchymal stem cell administration. Electrocardiography and echocardiography were recorded 2 weeks after the beginning of treatment. Rats were then sacrificed and the ventricle was isolated for estimation of tumor necrosis factor-alpha, vascular endothelial growth factor and transforming growth factor-beta. Moreover, protein expressions of caspase-3, connexin-43 as well as endothelial and inducible nitric oxide synthases were evaluated. Finally, histological studies of myocardial fibrosis and blood vessel density were performed and cryosections were done for estimation cell homing. Combined nicorandil/bone marrow-derived mesenchymal stem cell therapy provided an additional improvement compared to cell therapy alone toward reducing isoproterenol-induced cardiac hypertrophy, fibrosis and inflammation. Notably, combined therapy induced significant increase in angiogenesis and cell homing and prevented isoproterenol-induced changes in contractility and apoptotic markers. In conclusion, combined nicorandil/bone marrow-derived mesenchymal stem cell therapy was superior to cell therapy alone toward preventing isoproterenol-induced heart failure in rats through creation of a supportive environment for mesenchymal stem cells.

Bone marrow-derived stem cell therapy for metastatic brain cancers.

We propose that stem cell therapy may be a potent treatment for metastatic melanoma in the brain. Here we discuss the key role of a leaky blood-brain barrier (BBB) that accompanies the development of brain metastases. We review the need to characterize the immunological and inflammatory responses associated with tumor-derived BBB damage in order to reveal the contribution of this brain pathological alteration to the formation and growth of brain metastatic cancers. Next, we discuss the potential repair of the BBB and attenuation of brain metastasis through transplantation of bone marrow-derived mesenchymal stem cells with the endothelial progenitor cell phenotype. In particular, we review the need for evaluation of the efficacy of stem cell therapy in repairing a disrupted BBB in an effort to reduce neuroinflammation, eventually attenuating brain metastatic cancers. The demonstration of BBB repair through augmented angiogenesis and vasculogenesis will be critical to establishing the potential of stem cell therapy for the treatment/prevention of metastatic brain tumors. The overarching hypothesis we advanced here is that BBB breakdown is closely associated with brain metastatic cancers of melanoma, exacerbating the inflammatory response of the brain during metastasis, and ultimately worsening the outcome of metastatic brain cancers. Abrogating this leaky BBB-mediated inflammation via stem cell therapy represents a paradigm-shifting approach to treating brain cancer. This review article discusses the pros and cons of cell therapy for melanoma brain metastases.

Autologous bone marrow derived stem cell therapy in traumatic spinal cord injury: A case report and review of literature

Spinal cord injury (SCI) is a devastating condition. It not only creates enormous physical and emotional cost to the victims but also causes a financial burden to the society at large. The treatment of SCI focuses on preventing further injury and enabling people to return to an active and productive life within limits of their disability. Recently there is great excitement about the possibility of generating neural progenitor cells from sources such as mesenchymal cells derived from skin, bone-marrow, or adipose tissue. Stem cell therapy in traumatic spinal cord injury is an on going area of research in many centres in India and abroad. We describe a case of traumatic spinal cord injury with complete paraplegia in an adult where we had infused autologous bone marrow derived stem cell to damaged cord during fixation procedure and review the literature.

Role of bone marrow-derived stem cell therapy in treatment of experimentally induced type 1 diabetes mellitus in canine model

Background: Type 1 diabetes mellitus (DM) results from a cell-mediated autoimmune attack against pancreatic beta cells and characterized by severe damage to many tissues. Several in vitro studies have shown that bone marrow derived stem cells could be reprogrammed to become functionally insulin producing cells under certain culture conditions. Purpose: The aim of this study is to demonstrate that bone marrow derived mesenchymal stem cells (MSCs) can be induced to differentiate into insulin producing cells (IPCs) under suitable culture condition and to assess the ability of these differentiated cells to correct the functional defect in insulin secretion. Materials and methods: This study was done on 9 dogs, one as a negative control and 8 were induced to be diabetic. MSCs were isolated from bone marrow and induced to differentiate into IPCs. Two diabetic dogs received undifferentiated MSCs transplant, while another 2 diabetic dogs received differentiated MSCs and 1 diabetic dog remained as a positive control. Results: The diabetic dogs that received undifferentiated MSCs showed no improvement in FBG level during the observation period while the diabetic dogs that received differentiated MSCs showed improvement in FBG on day 6 after transplantation. Conclusion: This study suggests that bone marrow MSCs can be differentiate into IPCs that can improve FBG levels in diabetics.

Bone marrow-derived mesenchymal stem cell therapy for decompensated liver cirrhosis: a meta-analysis.

To assess the efficacy and safety of bone marrow-derived mesenchymal stem cell (BM-MSC) in the treatment of decompensated liver cirrhosis. The search terms "bone marrow stem cell" "chronic liver disease" "transfusion" and "injection" were used in the Cochrane Library, Med-Line (Pub-Med) and Embase without any limitations with respect to publication date or language. Journals were also hand-searched and experts in the field were contacted. The studies which used BM-MSC in the treatment of any chronic liver disease were included. Comprehensive Review Manager and Meta-Analyst software were used for statistical analysis. Publication bias was evaluated using Begg's test. Out of 78 studies identified, five studies were included in the final analysis. The studies were conducted in China, Iran, Egypt and Brazil. Analysis of pooled data of two controlled studies by Review Manager showed that the mean decline in scores for the model for end-stage liver disease (MELD) was -1.23 [95%CI: -2.45-(-0.01)], -1.87 [95%CI: -3.16-(-0.58)], -2.01 [95%CI: -3.35-(-0.68)] at 2, 4 and 24 wk, respectively after transfusion. Meta-analysis of the 5 studies showed that the mean improvement in albumin levels was -0.28, 2.60, 5.28, 4.39 g/L at the end of 8, 16, 24, and 48 wk, respectively, after transfusion. MELD scores, alanine aminotransferase, total bilirubin levels and prothrombin times improved to some extent. BM-MSC injections resulted in no serious adverse events or complications. BM-MSC infusion in the treatment of decompensated liver cirrhosis improved liver function. At the end of year 1, there were no serious side effects or complications.

Prompt bone marrow-derived mesenchymal stem cell therapy enables early porcine heart function recovery from acute myocardial infarction.

Impact of early bone marrow-derived mesenchymal stem cell (BMDMSC) implantation on left ventricular (LV) function after AMI was studied.Twelve mini-pigs were equally divided into placebo (AMI through left coronary artery ligation) and cell-treated groups [BMDMSCs (3.0 × 10(7)) implanted into infarct area (IA)] with myocardium harvested by post-AMI day 90. Six healthy animals served as controls.On post-AMI day 90, magnetic resonance imaging showed a lower LV ejection fraction but higher LV dimensions in the placebo group (P < 0.003) that also had increased IAs but reduced wall thickness (P < 0.005). Pro-apoptotic gene expressions (Bax, caspase-3) and apoptotic nucleus number in IAs and peri-IAs were highest in the placebo group (P < 0.001). Inflammatory biomarker expressions (MMP-9, oxidized protein, CD40+ cells) were highest, whereas those of angiogenesis (VEGF, CD31+ cells, SDF-1α, CXCR4) and myocardium-preservation (connexin43, troponin-I, cytochrome-C) were lowest in the placebo group (P < 0.01).BMDMSC implantation preserved LV function and alleviated remodeling at post-AMI day 90.

The principles of wound healing

Wound healing is an ever-changing field, as new insights are made into its mechanisms through basic science research, thus driving development of new therapies. In this paper, we present the current molecular models of wound healing and scar formation in the three phases: inflammation, proliferation and remodeling. New cellular signaling pathways such as mechanotransduction through the transforming growth factor-beta and integrin pathways have opened up various targets for wound therapy. Other therapies such as negative pressure devices and anti-microbial peptides are being improved as more data becomes available. Cutting edge treatments in gene therapy like Regranex are under heavy investigation, as are various treatments whose molecular mechanisms remain to be elucidated such as electrostimulation and Substance P. A promising area in wound treatment research is the use of bone marrow derived stem cell therapy, where research in animal models has shown these stem cells are able to differentiate into kera...

Autologous bone marrow-derived stem cell therapy in heart disease: discrepancies and contradictions.

Autologous bone marrow stem cell therapy is the greatest advance in the treatment of heart disease for a generation according to pioneering reports. In response to an unanswered letter regarding one of the largest and most promising trials, we attempted to summarise the findings from the most innovative and prolific laboratory. Amongst 48 reports from the group, there appeared to be 5 actual clinical studies ("families" of reports). Duplicate or overlapping reports were common, with contradictory experimental design, recruitment and results. Readers cannot always tell whether a study is randomised versus not, open-controlled or blinded placebo-controlled, or lacking a control group. There were conflicts in recruitment dates, criteria, sample sizes, million-fold differences in cell counts, sex reclassification, fractional numbers of patients and conflation of competitors' studies with authors' own. Contradictory results were also common. These included arithmetical miscalculations, statistical errors, suppression of significant changes, exaggerated description of own findings, possible silent patient deletions, fractional numbers of coronary arteries, identical results with contradictory sample sizes, contradictory results with identical sample sizes, misrepresented survival graphs and a patient with a negative NYHA class. We tabulate over 200 discrepancies amongst the reports. The 5 family-flagship papers (Strauer 2002, STAR, IACT, ABCD, BALANCE) have had 2665 citations. Of these, 291 citations were to the pivotal STAR or IACT-JACC papers, but 97% of their eligible citing papers did not mention any discrepancies. Five meta-analyses or systematic reviews covered these studies, but none described any discrepancies and all resolved uncertainties by undisclosed methods, in mutually contradictory ways. Meta-analysts disagreed whether some studies were randomised or "accepter-versus-rejecter". Our experience of presenting the discrepancies to journals is that readers may remain unaware of such problems. Modern reporting of clinical research can still be imperfect. The scientific literature absorbs such reports largely uncritically. Even meta-analyses seem to resolve contradictions haphazardly. Discrepancies communicated to journals are not guaranteed to reach the scientific community. Journals could consider prioritising systematic reporting of queries even if seemingly minor, and establishing a policy of "habeas data".

Intramyocardial Delivery of Mesenchymal Stem Cell-Seeded Hydrogel Preserves Cardiac Function and Attenuates Ventricular Remodeling after Myocardial Infarction

BackgroundTo improve the efficacy of bone marrow-derived mesenchymal stem cell (MSC) therapy targeted to infarcted myocardium, we investigated whether a self-setting silanized hydroxypropyl methylcellulose (Si-HPMC) hydrogel seeded with MSC (MSC+hydrogel) could preserve cardiac function and attenuate left ventricular (LV) remodeling during an 8-week follow-up study in a rat model of myocardial infarction (MI).Methodology/Principal FindingSi-HPMC hydrogel alone, MSC alone or MSC+hydrogel were injected into the myocardium immediately after coronary artery ligation in female Lewis rats. Animals in the MSC+hydrogel group showed an increase in cardiac function up to 28 days after MI and a mid-term prevention of cardiac function alteration at day 56. Histological analyses indicated that the injection of MSC+hydrogel induced a decrease in MI size and an increase in scar thickness and ultimately limited the transmural extent of MI. These findings show that intramyocardial injection of MSC+hydrogel induced short-term recovery of ventricular function and mid-term attenuation of remodeling after MI.Conclusion/SignificanceThese beneficial effects may be related to the specific scaffolding properties of the Si-HPMC hydrogel that may provide the ability to support MSC injection and engraftment within myocardium.

Removing the cells from adult bone marrow derived stem cell therapy does not eliminate cardioprotection†

The debate as to whether adult stem cell therapy is regenerative or not continues. The non-regenerative benefits of adult bone marrow-derived stem cell therapy were investigated by testing whether the supernatant derived from unfractionated bone marrow mononuclear cells might be cardioprotective in an animal model of myocardial ischaemia-reperfusion injury. Regional myocardial reperfusion injury was acquired by 25 min reversible left anterior descending coronary artery (LAD) occlusion followed by 2 h reperfusion, in anaesthetized Wistar male rats. Unfractionated bone marrow mononuclear cells (BMMNC) isolated from sibling Wistar male rat whole bone marrow were phenotyped by fluorescence activated cell sorting flowcytometry for the haematopoietic stem cell surface markers c-kit, CD34, CD45 and CD133. Animals subjected to regional myocardial reperfusion injury received either 10 million BMMNC or BMMNC supernatant (BMS); both were collected in 0.5 ml phosphate-buffered saline and delivered by intravenous bolus at the onset of reperfusion. The left ventricular region distal to the LAD occlusion point was excised for measurement of myocardial infarct size and proteomic analysis, which was used to identify whether there were any differences in myocardial proteins associated with intravenous injection of either BMMNC or BMS. BMMNC were phenotyped to be c-kit(+) (7 ± 1%), CD34(+) (7 ± 1%), CD45(+) (54 ± 6%), CD133(+) (15 ± 1%). The supernatant reduced myocardial infarct size (BMS 34 ± 2%, n = 15 vs control 57 ± 2%, n = 7, P < 0.0001), which was comparable to the reduction in infarct size afforded by the injection of cells (BMMNC 33 ± 3% vs control 57 ± 2%, n = 10, P < 0.0001). Proteomics of hearts treated with either BMS or BMMNC demonstrated higher expression of (i) anti-apoptotic signal transduction protein: 14-3-3-epsilon (1.5-fold); (ii) anti-oxidants: peroxiredoxin-6 (2.1-fold); (iii) heat shock proteins: alpha B-crystallin (1.7-fold), heat shock protein 72 (2.8-fold), tumour necrosis factor receptor-1 associated protein (2.3-fold), ischaemia responsive protein-94 (1.6-fold); (iv) glycolytic protein: glyceraldehyde-3-phosphate dehydrogenase (2.3-fold); (v) mitochondrial respiratory proteins: mitochondrial aconitase (4.7-fold), voltage-dependent anion-selective channel protein-1 (VDAC-1) (2.7-fold). Regional myocardial reperfusion injury can be attenuated by intravenous administration of either BMMNC or BMS at the onset of reperfusion, which suggests adult stem cells mediate non-regenerative cardioprotection.