Mesenchymal Stromal Cell Therapy Improves Refractory Perianal Fistula in Crohn's Disease: Case Series Clinical Interventional Study.

Objective: Perianal fistulas in Crohn's disease (CD) are the main challenges in inflammatory bowel diseases (IBDs). Some of the fistulas are refractory to any therapeutic strategy. The aim of this study was to evaluate the therapeutic effects of mesenchymal stromal cells (MSCs) as a novel promising modality for the treatment of fistulizing CD. Materials and Methods: This case series clinical interventional study was conducted from 2014 to 2017 at Shariati Hospital, an IBD referral center in Tehran, Iran. Refractory adult patients with CD who had draining perianal fistulas were enrolled in this study. All patients were examined by a colorectal surgeon and the fistula imaging studies were performed by pelvic magnetic resonance imaging (MRI). After autologous bone marrow (BM) aspiration and MSCs isolation, the cells were cultured and passaged under current good manufacturing practice (cGMP) conditions. Four intra-fistula injections of cells, each containing 40×106 MSCs suspended in fibrin glue, were administered by an expert surgeon every 4 weeks. Procedure safety, feasibility and closure of the perianal fistulas at week 24 were assessed. Clinical examination and MRI findings were considered as the primary end points. Results: In total, 5 patients (2 males and 3 females) were enrolled in this study. No adverse events were observed during the six-month follow-up in these patients. Both the Crohn's Disease Activity Index (CDAI) and Perianal Disease Activity Index (PDAI) scores decreased in all patients after cell injections and one patient achieved complete remission with closure of fistulas, discontinuation of fistula discharge, and closure of the external opening. Conclusion: Local injection of MSCs combined with fibrin glue is potentially a safe and effective therapeutic approach for complex perianal fistulas in patients with CD.

Safety and Efficacy of Allogeneic Adipose Tissue Mesenchymal Stromal Cells in Amyotrophic Lateral Sclerosis Patients, Single-Center, Prospective, Open-Label, Single-Arm Clinical Trial, Long-Term Follow-up.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with very limited treatment options. Stem cells have been raised as a new treatment modality for these patients. We have designed a single-center, prospective, open-label, and single arm clinical trial to assess the safety, feasibility, and rather efficacy of administrating allogeneic adipose-derived mesenchymal stromal cells (Ad-MSCs) in ALS patients. We enrolled 17 patients with confirmed ALS diagnosis with ALS Functional Rating Scale-Revised (ALSFRS-R) ≥24 and predicted forced vital capacity (FVC) ≥40%. Allogeneic Ad-MSCs were transplanted intravenously for all patients. Follow-ups were done at 24 hours, 2, 4, 6, and 12 months after cell infusion by checking adverse events, laboratory tests, and clinically by ALSFRS-R and FVC. Patients were also followed five years later and ALSFRS-R score was recorded in the survived individuals. There was no report of severe adverse events related to cell infusion. Two patients experienced dyspnea and chest pain 36 and 65 days after cell infusion due to pulmonary emboli. The progressive decrease in ALSFRS-R and FVC levels was recorded and three patients died in the first year. During five years follow up, despite a notable decrease in functional scores, 5 patients survived. Intravenous (IV) infusion of allogeneic Ad-MSCs in ALS patients is safe and feasible. The survival rate of the patients is more than IV autologous MSCs (Registration number: IRCT20080728001031N26).

Intra-articular knee implantation of autologous bone marrow-derived mesenchymal stromal cells in rheumatoid arthritis patients with knee involvement: Results of a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial.

BACKGROUND: In this study, we intend to assess the safety and tolerability of intra-articular knee implantation of autologous bone marrow-derived mesenchymal stromal cells (MSCs) in patients with rheumatoid arthritis (RA) and to determine the preliminary clinical efficacy data in this population. The trial registration numbers are as follows: Royan Institute Ethics Committee: AC/91/1133; NCT01873625. METHODS: This single-center, randomized, triple-blind, placebo-controlled phase 1/2 clinical trial randomized RA patients with knee involvement to receive either an intra-articular knee implantation of 40 million autologous bone marrow-derived MSCs per joint or normal saline (placebo). Patients were followed up for 12 months to assess therapy outcomes. RESULTS: A total of 30 patients, 15 in the MSC group and 15 in the placebo group, enrolled in this study. There were no adverse effects reported after MSC administration or during follow-up. Patients who received MSCs had superior findings according to the Western Ontario and McMaster Universities Arthritis Index (WOMAC), visual analogue scale (VAS), time to jelling and pain-free walking distance. However, this improvement could not be significantly sustained beyond 12 months. The MSC group exhibited improved standing time (P = 0.01). In addition, the MSCs appeared to contribute to reductions in methotrexate and prednisolone use. CONCLUSION: Intra-articular knee implantation of MSCs appeared to be safe and well tolerated. In addition, we observed a trend toward clinical efficacy. These results, in our opinion, have justified the need for further investigations over an extended assessment period with larger numbers of RA patients who have knee involvement.

Percutaneous Autologous Bone Marrow-Derived Mesenchymal Stromal Cell Implantation Is Safe for Reconstruction of Human Lower Limb Long Bone Atrophic Nonunion.

OBJECTIVE: Nonunion is defined as a minimum of a 9-month period of time since an injury with no visibly progressive signs of healing for 3 months. Recent studies show that application of mesenchymal stromal cells (MSCs) in the laboratory setting is effective for bone regeneration. Animal studies have shown that MSCs can be used to treat nonunions. For the first time in an Iranian population, the present study investigated the safety of MSC implantation to treat human lower limb long bone nonunion. MATERIALS AND METHODS: It is a prospective clinical trial for evaluating the safety of using autologus bone marrow derived mesenchymal stromal cells for treating nonunion. Orthopedic surgeons evaluated 12 patients with lower limb long bone nonunion for participation in this study. From these, 5 complied with the eligibility criteria and received MSCs. Under fluoroscopic guidance, patients received a one-time implantation of 20-50×106 MSCs into the nonunion site. All patients were followed by anterior-posterior and lateral X-rays from the affected limb, in addition to hematological, biochemical, and serological laboratory tests obtained before and 1, 3, 6, and 12 months after the implantation. Possible adverse effects that included local or systemic, serious or non-serious, and related or unrelated effects were recorded during this time period. RESULTS: From a safety perspective, all patients tolerated the MSCs implantation during the 12 months of the trial. Three patients had evidence of bony union based on the after implantation Xrays. CONCLUSION: The results have suggested that implantation of bone marrow-derived MSCs is a safe treatment for nonunion. A double-blind, controlled clinical trial is required to assess the efficacy of this treatment (Registration Number: NCT01206179).

Mesenchymal Stromal Cells Implantation in Combination with Platelet Lysate Product Is Safe for Reconstruction of Human Long Bone Nonunion.

OBJECTIVE: Nonunion is defined as a minimum of 9 months since injury without any visible progressive signs of healing for 3 months. Recent literature has shown that the application of mesenchymal stromal cells is safe, in vitro and in vivo, for treating long bone nonunion. The present study was performed to investigate the safety of mesenchymal stromal cell (MSC) implantation in combination with platelet lysate (PL) product for treating human long bone nonunion. MATERIALS AND METHODS: In this case series clinical trial, orthopedic surgeons visited eighteen patients with long bone nonunion, of whom 7 complied with the eligibility criteria. These patients received mesenchymal stromal cells (20 million cells implanted once into the nonunion site using a fluoroscopic guide) in combination with PL product. For evaluation of the effects of this intervention all the patients were followed up by taking anterior-posterior and lateral X-rays of the affected limb before and 1, 3, 6, and 12 months after the implantation. All side effects (local or systemic, serious or non-serious, related or unrelated) were observed during this time period. RESULTS: From a safety perspective the MSC implantation in combination with PL was very well tolerated during the 12 months of the trial. Four patients were healed; based on the control Xray evidence, bony union had occurred. CONCLUSION: Results from the present study suggest that the implantation of bone marrow-derived MSCs in combination with PL is safe for the treatment of nonunion. A double blind, controlled clinical trial is required to assess the efficacy of this treatment (Registration Number: NCT01206179).

Repeated Intraportal Injection of Mesenchymal Stem Cells in Combination with Pioglitazone in Patients with Compensated Cirrhosis: A Clinical Report of Two Cases.

BACKGROUND: Transplantation of mesenchymal stem cells (MSCs) in combination with pioglitazone, an agonist of peroxisome proliferator-activated receptor-γ (PPAR-γ), can reduce liver fibrosis in models of liver injury. In this study, we conducted a pilot study of intraportal infusion of autologous MSCs in combination with pioglitazone to assess safety, feasibility, and effectiveness in patients with compensated cirrhosis. METHODS: Two patients with compensated cirrhosis were enrolled in this study. Intraportal autologous bone marrow-derived MSCs were transplanted twice (6 months interval) to the patients. Meanwhile, 30 mg/day pioglitazone was prescribed for 12 months.  Patients were assessed at baseline and months 1, 3, 6, and 12 post-infusion. RESULTS: Procedural complications or any major adverse effects did not occur in this pilot study.  The patients' clinical conditions remained stable with no evidence of deterioration during the course of the study. A transient improvement in the Model for End-Stage Liver Disease (MELD) score was observed at month 3 post-infusion in one patient, which eventually returned to baseline at month 12. CONCLUSION: The combination of pioglitazone with MSCs is safe and feasible. The data justify further study of the combination therapy in cirrhotic patients.

Intraportal Infusion of Bone Marrow Mononuclear or CD133+ Cells in Patients With Decompensated Cirrhosis: A Double-Blind Randomized Controlled Trial.

UNLABELLED: The present study assessed the effects of intraportal infusions of autologous bone marrow-derived mononuclear cells (MNCs) and/or CD133+ cells on liver function in patients with decompensated cirrhosis. We randomly assigned 27 eligible patients to a placebo, MNCs, and/or CD133+ cells. Cell infusions were performed at baseline and month 3. We considered the absolute changes in the Model for End-Stage Liver Disease (MELD) scores at months 3 and 6 after infusion as the primary outcome. The participants and those who assessed the outcomes were unaware of the treatment intervention assignments. After 6 months, 9 patients were excluded because of liver transplantation (n=3), hepatocellular carcinoma (n=1), loss to follow-up (n=3), and death (n=2). The final analysis included 4 patients from the CD133+ group, 8 from the MNC group, and 6 from the placebo group. No improvement was seen in the MELD score at month 6 using either CD133+ cells or MNC infusions compared with placebo. However, at month 3 after infusion, a trend was seen toward a higher mean absolute change in the MELD score in patients who had received CD133+ cells compared with placebo (-2.00±1.87 vs. -0.13±1.46; p=.08). No significant adverse events occurred in the present study. A transient improvement in the MELD score was observed in subjects treated with CD133+ cells but not in the MNC or placebo group. Although the study was not powered to make definitive conclusions, the data justify further study of CD133+ therapy in cirrhotic patients. SIGNIFICANCE: Cell therapy is a new approach in liver disease. Several clinical experiments have been reported on the safety of bone marrow-derived stem cells to treat liver disorders. However, the effectiveness of these approaches in the long-term follow-ups of patients initiated controversial discussions among the scientific community. A double-blind randomized controlled trial was designed to address this concern scientifically. A transient improvement in the patients' signs occurred; however, for a sustainable result, more work is needed. The results of multiple administrations of cells reported in the present study can be compared with the results from other single-injection studies.

Surveillance for hepatocellular carcinoma after autologous stem cell transplantation in cirrhosis.

BACKGROUND: During the resent years there has been interest in using bone marrow stem cells to treat liver cirrhosis. However, there is a potential concern for malignant transformation after stem cell therapy. The aim of this study was to evaluate the development of hepatocellular carcinoma (HCC) after autologous bone marrow stem cell transplantation for liver cirrhosis. METHODS: All the patients who underwent autologous stem cell transplantation for liver cirrhosis between 2005 and 2011 at our center were enrolled. Cellular infusion was made through peripheral vein, portal vein, or hepatic artery.The patients were invited to undergo screening for hepatocellular carcinoma. The screening was made with ultrasonography and alpha-feto protein (AFP) measurement. RESULTS: Thirty two patients (18 males) were included in the study. Mean age of patients was 45.7 years. Fifteen patients (47%) received mesenchymal stem cell (MSC), 9 (28%) received bone marrow mononuclear cells, 5 (16%) were given CD 133-positive bone marrow cells, and 3 (9%) patients received CD 34-positive bone marrow cells. Mean duration of follow up was 20.5months. Mean serum level of AFP was 2.8 ng/ml at baseline and 3.4ng/ml at the end of follow up (p= 0.3). One patient was found to have hepatocellular carcinoma three months after infusion of bone marrow mononuclear cells. The incidence rate for HCC was 1.8 cases per 100 person-years in this study. CONCLUSION: Autologous bone marrow stem cell infusion does not appear to increase the risk of hepatocellular carcinoma. The incidence rate of HCC in this study is comparable or even less than the reported rates of HCC in cohort studies of cirrhotic patients.