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Repeated autologous bone marrow-derived mesenchymal stem cell injections improve radiation-induced proctitis in pigs.

ABSTRACT: The management of proctitis in patients who have undergone very-high-dose conformal radiotherapy is extremely challenging. The fibrosis-necrosis, fistulae, and hemorrhage induced by pelvic overirradiation have an impact on morbidity. Augmenting tissue repair by the use of mesenchymal stem cells (MSCs) may be an important advance in treating radiation-induced toxicity. Using a preclinical pig model, we investigated the effect of autologous bone marrow-derived MSCs on high-dose radiation-induced proctitis. Irradiated pigs received repeated intravenous administrations of autologous bone marrow-derived MSCs. Immunostaining and real-time polymerase chain reaction analysis were used to assess the MSCs' effect on inflammation, extracellular matrix remodeling, and angiogenesis, in radiation-induced anorectal and colon damages. In humans, as in pigs, rectal overexposure induces mucosal damage (crypt depletion, macrophage infiltration, and fibrosis). In a pig model, repeated administrations of MSCs controlled systemic inflammation, reduced in situ both expression of inflammatory cytokines and macrophage recruitment, and augmented interleukin-10 expression in rectal mucosa. MSC injections limited radiation-induced fibrosis by reducing collagen deposition and expression of col1a2/col3a1 and transforming growth factor-?/connective tissue growth factor, and by modifying the matrix metalloproteinase/TIMP balance. In a pig model of proctitis, repeated injections of MSCs effectively reduced inflammation and fibrosis. This treatment represents a promising therapy for radiation-induced severe rectal damage.

SUBMITTER: Linard C

PROVIDER: S-EPMC3808206 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Repeated autologous bone marrow-derived mesenchymal stem cell injections improve radiation-induced proctitis in pigs.

Linard Christine C Busson Elodie E Holler Valerie V Strup-Perrot Carine C Lacave-Lapalun Jean-Victor JV Lhomme Bruno B Prat Marie M Devauchelle Patrick P Sabourin Jean-Christophe JC Simon Jean-Marc JM Bonneau Michel M Lataillade Jean-Jacques JJ Benderitter Marc M

Stem cells translational medicine 20130925 11

The management of proctitis in patients who have undergone very-high-dose conformal radiotherapy is extremely challenging. The fibrosis-necrosis, fistulae, and hemorrhage induced by pelvic overirradiation have an impact on morbidity. Augmenting tissue repair by the use of mesenchymal stem cells (MSCs) may be an important advance in treating radiation-induced toxicity. Using a preclinical pig model, we investigated the effect of autologous bone marrow-derived MSCs on high-dose radiation-induced p ...[more]

PMID: 24068742

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Project description:UnlabelledStem cell therapy is an emerging alternative therapeutic or disease-modifying strategy for amyotrophic lateral sclerosis (ALS). The aim of this open-label phase I clinical trial was to evaluate the safety of two repeated intrathecal injections of autologous bone marrow (BM)-derived mesenchymal stromal cells (MSCs) in ALS patients. Eight patients with definite or probable ALS were enrolled. After a 3-month lead-in period, autologous MSCs were isolated two times from the BM at an interval of 26 days and were then expanded in vitro for 28 days and suspended in autologous cerebrospinal fluid. Of the 8 patients, 7 received 2 intrathecal injections of autologous MSCs (1 × 10(6) cells per kg) 26 days apart. Clinical or laboratory measurements were recorded to evaluate the safety 12 months after the first MSC injection. The ALS Functional Rating Scale-Revised (ALSFRS-R), the Appel ALS score, and forced vital capacity were used to evaluate the patients' disease status. One patient died before treatment and was withdrawn from the study. With the exception of that patient, no serious adverse events were observed during the 12-month follow-up period. Most of the adverse events were self-limited or subsided after supportive treatment within 4 days. Decline in the ALSFRS-R score was not accelerated during the 6-month follow-up period. Two repeated intrathecal injections of autologous MSCs were safe and feasible throughout the duration of the 12-month follow-up period.SignificanceStem cell therapy is an emerging alternative therapeutic or disease-modifying strategy for amyotrophic lateral sclerosis (ALS). To the authors' best knowledge, there are no clinical trials to evaluate the safety of repeated intrathecal injections of autologous bone marrow mesenchymal stromal cells in ALS. After the clinical trial (phase I/II) was conducted, the stem cell (HYNR-CS, NEURONATA-R) was included in the revision of the regulations on orphan drug designation (number 160; December 31, 2013) and approved as a New Drug Application (Department of Cell and Gene Therapy 233; July 30, 2014) by the Korean Food and Drug Administration. The phase II trial is expected to be reported later.

Project description:BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is a genetic ciliopathy disease characterized by progressive formation and enlargement of cysts in multiple organs. The kidneys are particularly affected and patients may eventually develop end-stage renal disease (ESRD). We hypothesize that bone marrow mesenchymal stromal cells (BMMSCs) are renotropic and may improve kidney function via anti-apoptotic, anti-fibrotic, and anti-inflammatory effects. In this study, we aim to assess the safety and tolerability of a BMMSC infusion in ADPKD patients.MethodsWe performed a single-arm phase I clinical trial with a 12-month follow-up. This study enrolled six eligible ADPKD patients with an estimated glomerular filtration rate (eGFR) of 25-60 ml/min/1.73 m2. Patients received autologous cultured BMMSCs (2 × 106 cells/kg) through the cubital vein according to our infusion protocol. We investigated safety issues and kidney function during the follow-up visits, and compared the findings to baseline and 1 year prior to the intervention.ResultsThere were no patients lost to follow-up. We observed no cell-related adverse events (AE) and serious adverse events (SAE) after 12 months of follow-up. The mean eGFR value of 33.8 ± 5.3 ml/min/1.73 m2 1 year before cell infusion declined to 26.7 ± 3.1 ml/min/1.73 m2 at baseline (P = 0.03) and 25.8 ± 6.2 ml/min/1.73 m2 at the 12-month follow-up visit (P = 0.62). The mean serum creatinine (SCr) level of 2 ± 0.3 mg/dl 1 year before the infusion increased to 2.5 ± 0.4 mg/dl at baseline (P = 0.04) and 2.5 ± 0.6 mg/dl at the 12-month follow-up (P = 0.96). This indicated significant changes between the differences of these two periods (12 months before infusion to baseline, and 12 months after infusion to baseline) in SCr (P = 0.05), but not eGFR (P = 0.09).ConclusionsThis trial demonstrated the safety and tolerability of an intravenous transplantation of autologous BMMSCs. BMMSC efficacy in ADPKD patients should be investigated in a randomized placebo-controlled trial with a larger population, which we intend to perform.Trial registrationClinicalTrials.gov, NCT02166489 . Registered on June 14, 2014.

Project description:BACKGROUND:Allogeneic and autologous bone marrow-derived mesenchymal stem cells (BMDMSCs) have been administered in equine joints for their anti-inflammatory effects. However, allogeneic BMDMSC offer multiple clinical and practical advantages. Therefore, it is important to determine the relative effectiveness of allogeneic vs autologous BMDMSCs. OBJECTIVES:The objective of the study was to compare the inflamed joint response to autologous vs allogeneic BMDMSCs injections, and to determine if either treatment generated an anti-inflammatory effect. STUDY DESIGN:Randomised controlled study. METHOD:Bone marrow was harvested from eight horses. Autologous BMDMSCs and pooled allogeneic BMDMSCs were culture expanded, cryopreserved and thawed immediately prior to administration. Ten million autologous BMDMSCs were administered with 75 ng rIL-1β into one tarsocrural joint and the contralateral tarsocrural joint received allogeneic BMDMSC plus 75 ng rIL-1β. Repeat injections were performed with the same treatment administered into the same joint. Four additional horses received 75 ng rIL-1β alone in a single tarsocrural joint. Clinical parameters (lameness, joint circumference and joint effusion) and synovial fluid parameters, including nucleated cell count (NCC), differential cell count, total protein (TP), prostaglandin E2 (PGE2 ) and C-reactive protein (CRP), were measured at baseline, 6, 12, 24, 72, 168 and 336 hours post-injection. RESULTS:No difference was detected between autologous and allogeneic treatment groups with respect to subjective lameness, joint effusion, joint circumference, NCC, TP, differential cell count, CRP or PGE2 . Neither autologous nor allogeneic treatments resulted in an improvement in clinical or cytological parameters over that elicited by rIL-1β alone. MAIN LIMITATIONS:A single dose of rIL-1β was evaluated and resulted in a severe synovitis which may have been too severe to observe a BMDMSC-mediated effect. CONCLUSIONS:This study revealed that allogeneic and autologous BMDMSCs resulted in an equivalent clinical and cytological response. Allogeneic and autologous BMDMSCs were equally ineffective in reducing the inflammatory response from acute rIL-1β-induced joint inflammation in horses.

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Repeated autologous bone marrow-derived mesenchymal stem cell injections improve radiation-induced proctitis in pigs.

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Repeated autologous bone marrow-derived mesenchymal stem cell injections improve radiation-induced proctitis in pigs.

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