Autologous Bone Marrow-derived Mesenchymal Stem Research Articles

Autologous bone marrow derived mesenchymal stem cells are safe for the treatment of Achilles tendinopathy

Achilles tendinopathy is a disabling condition that affects more than 50% of runners. Pre-clinical studies in a large animal model of naturally-occurring tendinopathy similar to human Achilles tendinopathy has shown benefits of autologous bone marrow-derived mesenchymal stem cell (MSC) implantation. However, MSCs are advanced therapies medicinal products (ATMPs), with strict regulatory requirements. Guided by the regulator we carried out a first in man study to assess the safety and efficacy of autologous MSC injection in human patients with non-insertional Achilles tendinopathy. Ten patients, mean age 47 with mid-portion Achilles tendon pain and swelling for more than 6 months, underwent autologous cultured cell injections (median 12.2 × 106, range 5–19 × 106 cells) into their Achilles tendon. At 24 weeks follow-up, no serious adverse reactions or important medical events were observed. MOXFQ, EQ-5D-5L, and VISA-A scores improved clinically at 12 and 24 weeks. VAS pain improved increasingly at 6, 12 and 24 weeks. MOXFQ Pain and VISA-A Scores improved > 12 points from baseline to 24 weeks in 8 patients. Maximum anteroposterior tendon thickness as measured by greyscale US decreased by mean 0.8 mm at 24 weeks. This phase IIa study demonstrated the safety of autologous MSC injection for non-insertional Achilles tendinopathy and provides proof-of-concept of the technique in patients, all of whom had previously failed conservative treatments for chronic disease and leads the way for a larger randomised controlled trial.

Autologous bone marrow-derived mesenchymal stem cells and endothelial progenitor cells transplantation showed potential benefits for type 2 diabetes mellitus Filipino patients: a case series

Autologous bone marrow-derived mesenchymal stem cells and endothelial progenitor cells transplantation showed potential benefits for type 2 diabetes mellitus Filipino patients: a case series

Cell-based tissue engineered flexor tendon allograft: A canine in vivo study.

This study aimed to compare the clinically established autologous extrasynovial tendon graft to a newly developed tissue-engineered allograft (Eng-allograft) in terms of functional outcomes following flexor tendon reconstruction in a canine model. The second and fifth flexor digitorum profundus (FDP) tendons from 16 dogs were transected and repaired in Zone II. After 6 weeks of cage activity, the repaired tendons were intentionally ruptured, creating a clinically relevant model for reconstruction. The re-ruptured FDP tendons were then reconstructed using either the clinically standard autologous extrasynovial tendon graft or the Eng-allograft, which had been revitalized with autologous bone marrow-derived mesenchymal stem cells (BMSCs) and synovialized using carbodiimide derivatized synovial fluid (cd-SYN). Following 12 weeks of postoperative rehabilitation, the functional outcomes of the surgical digits were evaluated. The Eng-allograft group exhibited improved digital function, including lower digit work of flexion and reduced adhesion status, while maintaining similar tendon gliding resistance compared to the autograft group. However, the failure load of both the distal and proximal host/graft conjunctions in the Eng-allograft group was significantly lower than that of the autograft group with higher graft rupture at the host-graft junction. In conclusion, the decellularized allogenic intrasynovial tendon, when revitalized BMSCs and synovialized with cd-SYN, demonstrates positive effects on digital function improvement and adhesion reduction. However, the healing at both proximal and distal graft/host junctions is far lower than the autograft. Further research is needed to enhance the healing capacity of allograft conjunctions, aiming to achieve a comparable level of healing seen with autografts.

Long-term survival benefits of intrathecal autologous bone marrow-derived mesenchymal stem cells (Neuronata-R®: lenzumestrocel) treatment in ALS: Propensity-score-matched control, surveillance study.

Neuronata-R® (lenzumestrocel) is an autologous bone marrow-derived mesenchymal stem cell (BM-MSC) product, which was conditionally approved by the Korean Ministry of Food and Drug Safety (KMFDS, Republic of Korea) in 2013 for the treatment of amyotrophic lateral sclerosis (ALS). In the present study, we aimed to investigate the long-term survival benefits of treatment with intrathecal lenzumestrocel. A total of 157 participants who received lenzumestrocel and whose symptom duration was less than 2 years were included in the analysis (BM-MSC group). The survival data of placebo participants from the Pooled-Resource Open-Access ALS Clinical Trials (PROACT) database were used as the external control, and propensity score matching (PSM) was used to reduce confounding biases in baseline characteristics. Adverse events were recorded during the entire follow-up period after the first treatment. Survival probability was significantly higher in the BM-MSC group compared to the external control group from the PROACT database (log-rank, p < 0.001). Multivariate Cox proportional hazard analysis showed a significantly lower hazard ratio for death in the BM-MSC group and indicated that multiple injections were more effective. Additionally, there were no serious adverse drug reactions found during the safety assessment, lasting a year after the first administration. The results of the present study showed that lenzumestrocel treatment had a long-term survival benefit in real-world ALS patients.

Treatment of racehorse superficial digital flexor tendonitis: A comparison of stem cell treatments to controlled exercise rehabilitation in 213 cases.

Overstrain of the superficial digital flexor tendon (SDFT) is a common Thoroughbred racehorse limb injury requiring treatment. To determine whether treatment of SDFT lesions in flat Thoroughbred racehorses with autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) or allogenic adipose-derived mesenchymal stem cells (A-MSCs) is associated with improved likelihood of returning to racing, when compared to racehorses managed with a controlled exercise rehabilitation program (CERP) alone. Retrospective cohort study combining clinical treatment records with race records. A total of 213 Thoroughbred racehorses were identified. All were prescribed the same 12-month CERP and 66 also received intralesional BM-MSC and 17 A-MSC treatment. Follow-up was a minimum of 2 years after return to full race training. Multivariable logistic regression models were used to investigate associations between the treatments and the likelihood of returning to racing and completing five or more (C5+) races post-injury. Compared to CERP alone, BM-MSC treatment was associated with increased odds of returning to racing (OR 3.19; 95% CI 1.55-6.81) and C5+ races post-injury (OR 2.64; 95% CI 1.32-5.33). Older age and increasing lesion length were associated with a reduced likelihood of returning to racing. Male sex and increased number of pre-injury starts were associated with increased odds of returning to racing. There was no observed increased likelihood of return to racing or C5+ races associated with treatment with A-MSCs compared to CERP alone. Due to the retrospective nature of the study it was not possible to ascertain how strictly the CERP was followed. Due to the novelty of the method, the A-MSC treatment group included a limited number of horses. In the study population, intralesional BM-MSC treatment was significantly associated with an increased likelihood of returning to racing and C5+ races post-injury compared to CERP alone. Intralesional A-MSC showed no significant association between treatment and the two investigated outcomes.

Randomized control trial of mesenchymal stem cells versus hyaluronic acid in patients with knee osteoarthritis - A Hong Kong pilot study.

ObjectiveThis pilot study evaluated the efficacy of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) versus hyaluronic acid (HA) in surgically naïve patients with knee osteoarthritis (OA).MethodsSingle-centre, single-blind randomized study of patients with knee OA. Twenty patients were randomized into groups of 10 each for intra-articular injection of cultured BM-MSCs (6 ​ml of BM-MSCs at 1 ​× ​106 ​cells/mL) or HA (6 ​ml). Clinical assessments of pain, quality of life, radiographic imaging, and magnetic resonance imaging (MRI) compositional change were performed at baseline and 12 months follow-up.ResultsCompared with HA, BM-MSCs injection resulted in significant improvement in qualify of life and reduction in pain as reflected by visual analogue scale (VAS) pain score, Western Ontario and McMaster Universities Arthritis Index (WOMAC) score, and 36-Item Short Form Survey (SF-36) score collectively. T2-relaxation time tended to decrease more in the BM-MSCs group with a 38 ​± ​24.0% reduction in 6 out of 10 BM-MSC participants; while there was only a 12 ​± ​7.9% reduction in 4 out of 10 HA participants at the end of follow-up. The remaining participants showed either no response or had relaxation time increased on MRI assessment.ConclusionsThis pilot study found that autologous BM-MSCs significantly reduced pain, improved functional assessment score, and improved quality of life parameters comparing with HA at one year follow-up. Further clinical trial with larger sample size and longer follow up duration is warranted.The Translational Potential of this ArticleThis pilot RCT demonstrated the feasibility and potential effectiveness of BM-MSCs advanced therapy for patients with knee OA compared to HA injection. Further multi-center clinical trial with a larger sample size and longer follow up duration in accordance with latest regulatory guidelines is warranted to ascertain the long term safety and effectiveness of MSCs therapy for cartilage regeneration in OA.RegistrationThe study was registered in the Centre for Clinical Research Biostatistics - Clinical Trials Registry (CUHK_CCT00469).

Efficacy and safety of Lenzumestrocel (Neuronata-R® inj.) in patients with amyotrophic lateral sclerosis (ALSUMMIT study): study protocol for a multicentre, randomized, double-blind, parallel-group, sham procedure-controlled, phase III trial

BackgroundA single cycle (two repeated treatments) with intrathecal autologous bone marrow-derived mesenchymal stem cells (BM-MSCs, 26-day interval) showed safety and provided therapeutic benefit lasting 6 months in patients with ALS but did not demonstrate long-term efficacy. This phase III clinical trial (ALSUMMIT) protocol was developed to evaluate the long-term efficacy and safety of the combined protocol of single-cycle intrathecal therapy and three additional booster injections of BM-MSC (Lenzumestrocel) treatment in patients with ALS.MethodsALSUMMIT is a multicentre, randomized, double-blind, parallel-group, sham procedure-controlled, phase III trial for ALS. The 115 subjects will be randomized (1:2:2) into three groups: (1) study Group 1 (single-cycle, two repeated injections with 26-day interval), (2) study Group 2 (single-cycle + three additional booster injections at 4, 7, and 10 months), and (3) the control group. Participants who have an intermediate rate of disease progression will be included in this trial to reduce clinical heterogeneity. The primary endpoint will be evaluated by combined assessment of function and survival (CAFS), also known as joint rank scores (JRS), at 6 months (study Group 1 vs. control) and 12 months (study Group 2 vs. control) after the first Lenzumestrocel or placebo administration. Safety assessment will be performed throughout the study period. Additionally, after the 56-week main study, a long-term follow-up observational study will be conducted to evaluate the long-term efficacy and safety up to 36 months.DiscussionLenzumestrocel is the orphan cell therapy product for ALS conditionally approved by the South Korea Ministry of Food and Drug Safety (MFDS). This ALSUMMIT protocol was developed for the adoption of enrichment enrolment, add-on design, and consideration of ethical issues for the placebo group.Trial registrationClinicalTrials.govNCT04745299. Registered on Feb 9, 2021.Clinical Research Information Service (CRIS) KCT0005954. Registered on Mar 4, 2021.

The Emerging Role of Non-Coding RNAs in Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells.

Autologous bone marrow-derived mesenchymal stem cells (BMSCs) are more easily available and frequently used for bone regeneration in clinics. Osteogenic differentiation of BMSCs involves complex regulatory networks affecting bone formation phenomena. Non-coding RNAs (ncRNAs) refer to RNAs that do not encode proteins, mainly including microRNAs, long non-coding RNAs, circular RNAs, piwi-interacting RNAs, transfer RNA-derived small RNAs, etc. Recent in vitro and in vivo studies had revealed the regulatory role of ncRNAs in osteogenic differentiation of BMSCs. NcRNAs had both stimulatory and inhibitory effects on osteogenic differentiation of BMSCs. During the physiological condition, osteo-stimulatory ncRNAs are upregulated and osteo-inhibitory ncRNAs are downregulated. The opposite effects might occur during bone degenerative disease conditions. Intracellular ncRNAs and ncRNAs from neighboring cells delivered via exosomes participate in the regulatory process of osteogenic differentiation of BMSCs. In this review, we summarize the recent advances in the regulatory role of ncRNAs on osteogenic differentiation of BMSCs during physiological and pathological conditions. We also discuss the prospects of the application of modulation of ncRNAs function in BMSCs to promote bone tissue regeneration in clinics.

Role of bone marrow-derived mesenchymal stem cells in treatment avascular necrosis of femoral head

Avascular necrosis (AVN) of the femoral head (FH) is a debilitating and painful disease with multiple etiologic risk factors head shows an increasing tendency and most commonly affects younger or middle-aged adults. Fifty patients (55 hips) with stage I, II or III avascular necrosis of femoral head were treated by autologous Bone marrow-derived mesenchymal stem cells injection. The patients were followed up clinically and radiologically for a minimum of 2 years at baseline, three, six, 12, and 24 months. The functional outcome was assessed in terms of Harris hip score, and disease progression was assessed radiologically by comparing the preoperative and follow-up MRI at the end of 2 years. On 2-year follow-up, there was considerable improvement in the hip function as measured by the Harris hip score (p = 0.041). On MRI, there was a decrease in the size of the lesion in group A (p = 0.03). Our findings showed that autologous Bone marrow-derived mesenchymal stem cells in avascular necrosis of femoral head is a safe and effective procedure and has better outcome.

Role of bone marrow-derived mesenchymal stem cells in treatment avascular necrosis of femoral head

Avascular necrosis (AVN) of the femoral head (FH) is a debilitating and painful disease with multiple etiologic risk factors head shows an increasing tendency and most commonly affects younger or middle-aged adults. Fifty patients (55 hips) with stage I, II or III avascular necrosis of femoral head were treated by autologous Bone marrow-derived mesenchymal stem cells injection. The patients were followed up clinically and radiologically for a minimum of 2 years at baseline, three, six, 12, and 24 months. The functional outcome was assessed in terms of Harris hip score, and disease progression was assessed radiologically by comparing the preoperative and follow-up MRI at the end of 2 years. On 2-year follow-up, there was considerable improvement in the hip function as measured by the Harris hip score (p = 0.041). On MRI, there was a decrease in the size of the lesion in group A (p = 0.03). Our findings showed that autologous Bone marrow-derived mesenchymal stem cells in avascular necrosis of femoral head is a safe and effective procedure and has better outcome.

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.

"Autologous Bone Marrow-Derived Mesenchymal Stem Cells for Tendon Repair in Horses: Experimental Study"

Tendon lesions are a major cause of lameness and reduced performance in athletic horses and may result in the early termination of the animal’s career with subsequent significant economic loss and animal welfare

Phase I Trial of Intra-arterial Administration of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Patients with Multiple System Atrophy.

Background This study is aimed at investigating the safety and tolerability of the intra-arterial administration of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with multiple system atrophy- (MSA-) cerebellar type (MSA-C). Methods This was a single-center, open-label phase I clinical trial in patients with MSA-C. A three-stage dose escalation scheme (low-dose, 3.0 × 105 cells/kg; medium-dose, 6.0 × 105 cells/kg; high-dose, 9.0 × 105 cells/kg) was applied to determine the maximum tolerated dose of intra-arterial administration of BM-MSCs based on the no-observed-adverse-effect level derived from the toxicity study. The occurrence of adverse events was evaluated 1 day before and 1, 14, and 28 days after BM-MSC therapy. Additionally, we assessed changes in the Unified MSA Rating Scale (UMSARS) score 3 months after BM-MSC treatment. Results One serious adverse drug reaction (ADR) of leptomeningeal enhancement following the intra-arterial BM-MSC administration occurred in one patient in the low-dose group. The safety review of the Internal Monitoring Committee interpreted this as radiological evidence of the blood-brain barrier permeability for MSCs. No other ADRs were observed in the medium- or high-dose groups. In particular, no ischemic lesions on diffusion-weighted images were observed in any of the study participants. Additionally, the medium- and high-dose groups tended to show a slower increase in UMSARS scores than the low-dose group during the 3-month follow-up. Conclusion The present study confirmed that a single intra-arterial administration of autologous BM-MSCs is a safe and promising neuroprotective strategy in patients with MSA-C.

Autologous bone marrow-derived mesenchymal stem cells provide complete regeneration in a rabbit model of the Achilles tendon bundle rupture.

To ascertain the role of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in the tendon regeneration. The study was conducted on 58 Achilles tendons from 29 laboratory Chinchilla adult rabbits. The central bundles of 48 tendons were partially removed and substituted with a tissue-engineered construct consisting of a collagen sponge either loaded with BM-MSCs (n = 24) or cell free (n = 24), placed inside a Vicryl mesh tube. The ends of the resected tendon were inserted in the construct to reach a direct contact with the sponge and sutured to the tube. The animals were sacrificed three and sixmonths post-surgery. Ten intact tendons from five rabbits were used as an untreated control. The tissue samples (n = 30) were stained with haematoxylin and eosin, Picrosirius red, primary antibodies to collagen types I and III and studied by bright-field, phase-contrast, polarized light, and scanning electron microscopies followed by semi-quantitative morphometry. Six months results of cell-loaded scaffolds demonstrated parallel collagen fibres, spindle-shaped tenocytes, and neoangiogenesis. In the control cell-free group, the injured areas were filled with a nonspecific fibrotic tissue with minor foci of incomplete regeneration. The biomechanical tests of 28 tendons taken from 14 rabbits showed that the stiffness of the cell-based reconstructed tendons increased to 98% of the value for the intact samples. The obtained results support the hypothesis that the application of BM-MSCs in a tissue-engineered tendon construct leads to the restitution of the tendon tissue.

Safety and efficacy of bone marrow derived-mesenchymal stem cells transplantation in patients with amyotrophic lateral sclerosis.

Stem cell-based treatments have emerged as potentially effective approaches to delay the progression of amyotrophic lateral sclerosis (ALS). This study was designed as a single-center, prospective, and open-label study without a placebo control group to assess the safety and efficacy of concurrent intrathecal (IT) and intravenous (IV) administration of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with ALS. Autologous BM-MSCs were isolated and expanded under standard conditions. Fifteen patients were neurologically examined before BM-MSCs transplantation (1 × 10 6 cells/kg BW) to evaluate the rate of pre-treatment disease progression. To assess the safety and efficacy, patients were examined at 1, 3, and 6 months following the treatment with BM-MSCs. Adverse reactions were assessed, and the clinical outcome was determined by the evaluation of the ALS functional rating scale-revised (ALSFRS-R) and forced vital capacity (FVC). No serious adverse reaction was observed after combined IT and IV administration of BM-MSCs. The mean ALSFRS-R and FVC values remained stable during the first 3 months of the treatment. However, a significant reduction in ALSFRS-R and FVC levels was observed in these patients 6 months after BM-MSCs administration. Our study revealed that the concurrent IT and IV application of BM-MSCs in patients with ALS is a safe procedure. Furthermore, our data indicate a temporary delay in the progression of ALS after a single combined IT and IV administration of BM-MSCs. Further studies are required to explore if the repeated applications of BM-MSCs could prolong survival and delay the progression of ALS.

Combining cell therapy with human autologous Schwann cell and bone marrow-derived mesenchymal stem cell in patients with subacute complete spinal cord injury: safety considerations and possible outcomes

BackgroundCellular transplantations have promising effects on treating spinal cord injury (SCI) patients. Mesenchymal stem cells (MSCs) and Schwann cells (SCs), which have safety alongside their complementary characteristics, are suggested to be the two of the best candidates in SCI treatment. In this study, we assessed the safety and possible outcomes of intrathecal co-transplantation of autologous bone marrow MSC and SC in patients with subacute traumatic complete SCI.MethodsEleven patients with complete SCI (American Spinal Injury Association Impairment Scale (AIS); grade A) were enrolled in this study during the subacute period of injury. The patients received an intrathecal autologous combination of MSC and SC and were followed up for 12 months. We assessed the neurological changes by the American Spinal Injury Association’s (ASIA) sensory-motor scale, functional recovery by spinal cord independence measure (SCIM-III), and subjective changes along with adverse events (AE) with our checklist. Furthermore, electromyography (EMG), nerve conduction velocity (NCV), magnetic resonance imaging (MRI), and urodynamic study (UDS) were conducted for all the patients at the baseline, 6 months, and 1 year after the intervention.ResultsLight touch AIS score alterations were approximately the same as the pinprick changes (11.6 ± 13.1 and 12 ± 13, respectively) in 50% of the cervical and 63% of the lumbar-thoracic patients, and both were more than the motor score alterations (9.5 ± 3.3 in 75% of the cervical and 14% of the lumbar-thoracic patients). SCIM III total scores (21.2 ± 13.3) and all its sub-scores (“respiration and sphincter management” (15 ± 9.9), “mobility” (9.5 ± 13.3), and “self-care” (6 ± 1.4)) had statistically significant changes after cell injection. Our findings support that the most remarkable positive, subjective improvements were in trunk movement, equilibrium in standing/sitting position, the sensation of the bladder and rectal filling, and the ability of voluntary voiding. Our safety evaluation revealed no systemic complications, and radiological images showed no neoplastic overgrowth, syringomyelia, or pseudo-meningocele.ConclusionThe present study showed that autologous SC and bone marrow-derived MSC transplantation at the subacute stage of SCI could reveal statistically significant improvement in sensory and neurological functions among the patients. It appears that using this combination of cells is safe and effective for clinical application to spinal cord regeneration during the subacute period.

Safety of autologous bone marrow-derived mesenchymal stem cells in erectile dysfunction: an open-label phase 1 clinical trial

Background aimsThe efficacy of phosphodiesterase type 5 inhibitors (PDE5Is), which are commonly used to treat erectile dysfunction (ED), is not satisfactory in patients with denervation of the cavernous nerve due to pelvic surgeries and diabetes mellitus (DM). Pre-clinical studies using bone marrow-derived mesenchymal stem cells (BMSCs) to treat ED have shown promising results. The authors conducted a phase 1 clinical trial with autologous BMSCs in patients with ED due to radical prostatectomy or DM. MethodsTen patients (five with post-prostatectomy ED and five with DM-associated ED) who could not perform sexual activity despite taking the maximum dose of a PDE5I were enrolled. The brief clinical trial protocol was registered with the US National Institutes of Health on ClinicalTrials.gov (NCT02344849). The primary outcome was the safety of stem cell therapy, and the secondary outcome was the improvement of erectile function. ResultsOf the 13 patients screened, 10 were registered in the clinical trial and received autologous BMSCs and nine completed the clinical trial. One patient with post-prostatectomy ED experienced two treatment-emergent adverse events (TEAEs) (pyrexia and back pain), and two patients with DM-associated ED experienced a total of five TEAEs (one case each of viral upper respiratory tract infection, prostatitis and pruritus and two cases of hyperglycemia). Of these patients, one with DM-associated ED experienced two serious TEAEs (two instances of hyperglycemia). All TEAEs were considered not to be related to autologous BMSC therapy. In addition, no clinical significance was identified related to other safety measures, such as laboratory tests and vital signs. The mean International Index of Erectile Function score increased significantly at 1 month versus baseline (24.9 versus 18.1, P = 0.0222). ConclusionsThis phase 1 clinical trial confirmed the safety and potential efficacy of autologous BMSC therapy in patients with ED. The authors’ results need to be confirmed by a phase 2 clinical trial.

Osthole enhances the immunosuppressive effects of bone marrow‐derived mesenchymal stem cells by promoting the Fas/FasL system

Thanks to the advantages of easy harvesting and escape from immune rejection, autologous bone marrow‐derived mesenchymal stem cells (BMSCs) are promising candidates for immunosuppressive therapy against inflammation and autoimmune diseases. However, the therapy is still challenging because the immunomodulatory properties of BMSCs are always impaired by immunopathogenesis in patients. Because of its reliable and extensive biological activities, osthole has received increased clinical attention. In this study, we found that BMSCs derived from osteoporosis donors were ineffective in cell therapy for experimental inflammatory colitis and osteoporosis. In vivo and in vitro tests showed that because of the down‐regulation of Fas and FasL expression, the ability of osteoporotic BMSCs to induce T‐cell apoptosis decreased. Through the application of osthole, we successfully restored the immunosuppressive ability of osteoporotic BMSCs and improved their treatment efficacy in experimental inflammatory colitis and osteoporosis. In addition, we found the immunomodulatory properties of BMSCs were enhanced after osthole pre‐treatment. In this study, our data highlight a new approach of pharmacological modification (ie osthole) to improve the immune regulatory performance of BMSCs from a healthy or inflammatory microenvironment. The development of targeted strategies to enhance immunosuppressive therapy using BMSCs may be significantly improved by these findings.

Autologous bone marrow-derived mesenchymal stem cells for interstitial fibrosis and tubular atrophy: a pilot study

Background Mesenchymal stem cells (MSCs)-based therapy has shown promising results for renal injury. In this study, the efficacy and safety of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in treating nonspecific interstitial fibrosis and tubular atrophy (IFTA) were evaluated. Methods From March 2011 to January 2013, 11 renal transplanted patients with IFTA were recruited. At baseline, patients were given one intra-arterial infusion of BM-MSCs; 7 days and 1 month later, another two intravenous infusions of cells were followed. Serum creatinine, creatinine clearance rate, and serum cystatin-C at baseline and 7 days, 1 month, 3 months, 6 months, and 12 months after the intra-arterial infusion of BM-MSCs were used to assess renal function. At baseline and 6 months, histological examination based on hematoxylin-eosin, Masson’s trichrome and periodic acid-Schiff staining and immunohistochemistry for transforming growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF) was performed. Adverse events were recorded to evaluate the safety of BM-MSCs treatment. Results At 12 months, the renal function of 6 patients (54.5%) was improved, 3 (27.3%) were stable and 2 (18.2%) were worsened. At 6 months, the mean IFTA scores of all participators were similar with the baseline (1.73 ± 0.41 vs.1.50 ± 0.0.77, p = 0.242); however, it was significantly decreased when only 6 patients with improved renal function were analyzed (1.67 ± 0.41 vs. 1.08 ± 0.20, p = 0.013). Besides, decreased expression of TGF-β1 and CTGF were also observed at 6 months. During 1 year follow-up period, only two minor complications including infection and allergy were observed. Conclusion Our results demonstrated that autologous BM-MSCs are safe and beneficial for IFTA patients. Abbreviations: MSCs: mesenchymal stem cells; BM-MSCs: marrow-derived mesenchymal stem cells; IFTA: interstitial fibrosis and tubular atrophy; CAN: chronic allograft nephropathy; CNIs: calcineurin inhibitors; Scr: serum creatinine; CCr: creatinine clearance rate; Cys-C: cystatin-C; TGF-β1: transforming growth factor β1; CTGF: connective tissue growth factor

The effect of bone marrow-derived stem cells associated with platelet-rich plasma on the osseointegration of immediately placed implants.

BackgroundStem cells associated with growth factors have been shown to improve bone healing and the osseointegration of dental implants. A Brazilian miniature pig model was used to evaluate the effect of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) associated with platelet-rich plasma (PRP) on the osseointegration of immediately placed dental implants. Material and MethodsA total of four male adult miniature pigs were used in this study. BM-MSCs from each pig were isolated from the iliac crest and expanded in vitro. The undifferentiated BM-MSCs were mixed with autologous PRP and implanted in the post-extraction sockets at the experimental sites before implant placement (10 x 106 cells/ socket). The control sites did not receive either BM-MSC or PRP. Each animal received four implants in the control side and 04 on the experimental side, totalizing 32 implants. The specimens were analyzed radiographically and histomorphometrically to determine the implant loss rate (ILR), the bone-implant contact (BIC), and bone density within the threads (BDWT). ResultsThe ILR, the BIC, and the BDWT for the control and experimental sites were respectively 25.0% and 18.7% (p=0.686); 39.0% and 27.7% (p=0.110); 46.8% and 36.5% (p=0.247). ConclusionsThe use of BM-MSCs + PRP in conjunction with immediately placed implants showed a lower ILR but there was no significant effect on the osseointegration of the dental implants. More preclinical studies, in large animal models, are needed to establish whether BM-MSCs associated with PRP could be used for the enhancement of the osseointegration of dental implants. Key words:Osseointegration, bone marrow-derived mesenchymal stem cells, platelet-rich plasma, dental implants, minipigs.