Intrathecal Transplantation of Autologous and Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells in Dogs.
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ABSTRACT:
SUBMITTER: Benavides FP
PROVIDER: S-EPMC8388229 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cell therapy is being widely explored in the management of stroke and has demonstrated great potential. It has been shown to assist in the remodeling of the central nervous system by inducing neurorestorative effect through the process of angiogenesis, neurogenesis, and reduction of glial scar formation. In this study, the effect of intrathecal administration of autologous bone marrow mononuclear cells (BMMNCs) is analyzed on the recovery process of patients with chronic stroke. 24 patients diagnosed with chronic stroke were administered cell therapy, followed by multidisciplinary neurorehabilitation. They were assessed on functional independence measure (FIM) objectively, along with assessment of standing and walking balance, ambulation, and hand functions. Out of 24 patients, 12 improved in ambulation, 10 in hand functions, 6 in standing balance, and 9 in walking balance. Further factor analysis was done. Patients of the younger groups showed higher percentage of improvement in all the areas. Patients who underwent cell therapy within 2 years after the stroke showed better changes. Ischemic type of stroke had better recovery than the hemorrhagic stroke. This study demonstrates the potential of autologous BMMNCs intrathecal transplantation in improving the prognosis of functional recovery in chronic stage of stroke. Further clinical trials are recommended. This trial is registered with NCT02065778.
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Project description:There is a need among patients suffering from drug-resistant epilepsy (DRE) for more efficient and less toxic treatments. The objective of the present study was to assess the safety, feasibility, and potential efficacy of autologous bone marrow cell transplantation in pediatric patients with DRE. Two females and two males (11 months to 6 years) were enrolled and underwent a combined therapy consisting of autologous bone marrow nucleated cells (BMNCs) transplantation (intrathecal: 0.5 × 109 ; intravenous: 0.38 × 109 -1.72 × 109 ) followed by four rounds of intrathecal bone marrow mesenchymal stem cells (BMMSCs) transplantation (18.5 × 106 -40 × 106 ) every 3 months. The BMMSCs used were a unique population derived from CD271-positive cells. The neurological evaluation included magnetic resonance imaging, electroencephalography (EEG), and cognitive development assessment. The characteristics of BMMSCs were evaluated. Four intravenous and 20 intrathecal transplantations into the cerebrospinal fluid were performed. There were no adverse events, and the therapy was safe and feasible over 2 years of follow-up. The therapy resulted in neurological and cognitive improvement in all patients, including a reduction in the number of epileptic seizures (from 10 per day to 1 per week) and an absence of status epilepticus episodes (from 4 per week to 0 per week). The number of discharges on the EEG evaluation was decreased, and cognitive improvement was noted with respect to reactions to light and sound, emotions, and motor function. An analysis of the BMMSCs' characteristics revealed the expression of neurotrophic, proangiogenic, and tissue remodeling factors, and the immunomodulatory potential. Our results demonstrate the safety and feasibility of BMNCs and BMMSCs transplantations and the considerable neurological and cognitive improvement in children with DRE. Stem Cells Translational Medicine 2018;7:20-33.
| S-EPMC5746144 | biostudies-literature
Project description:Mid-substance rupture of the canine cranial cruciate ligament rupture (CR) and associated stifle osteoarthritis (OA) is an important veterinary health problem. CR causes stifle joint instability and contralateral CR often develops. The dog is an important model for human anterior cruciate ligament (ACL) rupture, where rupture of graft repair or the contralateral ACL is also common. This suggests that both genetic and environmental factors may increase ligament rupture risk. We investigated use of bone marrow-derived mesenchymal stem cells (BM-MSCs) to reduce systemic and stifle joint inflammatory responses in dogs with CR. Twelve dogs with unilateral CR and contralateral stable partial CR were enrolled prospectively. BM-MSCs were collected during surgical treatment of the unstable CR stifle and culture-expanded. BM-MSCs were subsequently injected at a dose of 2x106 BM-MSCs/kg intravenously and 5x106 BM-MSCs by intra-articular injection of the partial CR stifle. Blood (entry, 4 and 8 weeks) and stifle synovial fluid (entry and 8 weeks) were obtained after BM-MSC injection. No adverse events after BM-MSC treatment were detected. Circulating CD8+ T lymphocytes were lower after BM-MSC injection. Serum C-reactive protein (CRP) was decreased at 4 weeks and serum CXCL8 was increased at 8 weeks. Synovial CRP in the complete CR stifle was decreased at 8 weeks. Synovial IFN? was also lower in both stifles after BM-MSC injection. Synovial/serum CRP ratio at diagnosis in the partial CR stifle was significantly correlated with development of a second CR. Systemic and intra-articular injection of autologous BM-MSCs in dogs with partial CR suppresses systemic and stifle joint inflammation, including CRP concentrations. Intra-articular injection of autologous BM-MSCs had profound effects on the correlation and conditional dependencies of cytokines using causal networks. Such treatment effects could ameliorate risk of a second CR by modifying the stifle joint inflammatory response associated with cranial cruciate ligament matrix degeneration or damage.
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Project description:Allogeneic hematopoietic stem cell transplantation (HSCT) is a technologically complicated procedure that represents the only cure for many hematologic malignancies. However, HSCT is often complicated by life-threatening toxicities related to the chemo-radiation conditioning regimen, poor engraftment of donor HSCs, the hyperinflammatory syndrome of graft-versus-host disease (GVHD), infection risks from immunosuppression, and end-organ damage. Bone marrow stromal cells (MSCs), also known as "mesenchymal stromal cells," not only play a nurturing role in the hematopoietic microenvironment but also can differentiate into other cell types of mesenchymal origin. MSCs are poorly immunogenic, and they can modulate immunological responses through interactions with a wide range of innate and adaptive immune cells to reduce inflammation. They are easily expanded ex vivo and after infusion, home to sites of injury and inflammation to promote tissue repair. Despite promising early trial results in HSCT with significant responses that have translated into survival benefits, there have been significant barriers to successful commercialization as an off-the-shelf therapy. Current efforts with MSCs in the HSCT setting are geared toward determining the factors determining potency, understanding the precise mechanisms of action in human HSCT, knowing their kinetics and fate, optimizing dose and schedule, incorporating biomarkers as response surrogates, addressing concerns about safety, optimizing clinical trial design, and negotiating the uncharted regulatory landscape for licensable cellular therapy.
| S-EPMC4030656 | biostudies-literature
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.
| S-EPMC4449093 | biostudies-literature
Project description:BackgroundNeuroinflammation plays a key role in PD pathogenesis, and allogeneic bone marrow-derived mesenchymal stem cells can be used as an immunomodulatory therapy.ObjectiveThe objective of this study was to prove the safety and tolerability of intravenous allogeneic bone marrow-derived mesenchymal stem cells in PD patients.MethodsThis was a 12-month single-center open-label dose-escalation phase 1 study of 20 subjects with mild/moderate PD assigned to a single intravenous infusion of 1 of 4 doses: 1, 3, 6, or 10 × 106 allogeneic bone marrow-derived mesenchymal stem cells/kg, evaluated 3, 12, 24, and 52 weeks postinfusion. Primary outcome safety measures included transfusion reaction, study-related adverse events, and immunogenic responses. Secondary outcomes included impact on peripheral markers, PD progression, and changes in brain perfusion.ResultsThere were no serious adverse reactions related to the infusion and no responses to donor-specific human leukocyte antigens. Most common treatment-emergent adverse events were dyskinesias (20%, n = 4) with 1 emergent and 3 exacerbations; and hypertension (20%, n = 4) with 3 transient episodes and 1 requiring medical intervention. One possibly related serious adverse event occurred in a patient with a 4-year history of lymphocytosis who developed asymptomatic chronic lymphocytic leukemia. Peripheral inflammation markers appear to be reduced at 52 weeks in the highest dose including, tumor necrosis factor-α (P < 0.05), chemokine (C-C motif) ligand 22 (P < 0.05), whereas brain-derived neurotrophic factor (P < 0.05) increased. The highest dose seems to have demonstrated the most significant effect at 52 weeks, reducing the OFF state UPDRS motor, -14.4 (P < 0.01), and total, -20.8 (P < 0.05), scores.ConclusionA single intravenous infusion of allogeneic bone marrow-derived mesenchymal stem cells at doses of 1, 3, 6, or 10 × 106 allogeneic bone marrow-derived mesenchymal stem cells/kg is safe, well tolerated, and not immunogenic in mild/moderate PD patients. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
| S-EPMC8451899 | biostudies-literature
Project description:Mesenchymal stromal cells (MSCs) have become the most commonly used adult stem cells in regenerative medicine. Preclinical studies have shown that MSCs-based therapy is a potential new treatment approach for neurological diseases. Intrathecal injection has unique feature which allows stem cells to directly migrate to the lesion site in patients with central nervous system (CNS) diseases. In this study, we evaluate the safety and feasibility of intrathecal allogeneic bone marrow-derived MSCs (BM-MSCs) in patients with neurological diseases. This open-label clinical study included 37 patients (14 diseases). Eligible patients underwent a baseline assessment and were intrathecally injected with allogeneic BM-MSCs (1 × 106 cells/kg, 4 consecutive treatments at 1-week intervals). After four infusions, the patients were followed up for at least 6 months. Adverse events, cerebrospinal fluid (CSF) test results, clinical symptoms, physical examination, and haematological and imaging examinations were used to assess the safety and feasibility of the treatment. Also, we performed a systematic review of the safety of all types of intrathecal stem cells and compared our result to previous studies. In our study, the highest adverse event was a slight ache at the injection site (4.11%), followed by fever (3.42%) and mild headache (2.05%). No severe adverse events were reported. After the intrathecal injections, the white blood cell (WBC) counts in the CSF increased in 30 patients and the protein concentration in the CSF exceeded the normal range in 26 patients, while other CSF indicators remained normal. Moreover, these patients had no suspected manifestations of CNS infection. Haematological and imaging examinations showed no abnormal changes after BM-MSCs infusion. Compared with previous studies, the incidence of adverse events was nearly consistent or even lower for headache, fever, nausea, and neck pain. In conclusion, repeated intrathecal allogeneic BM-MSCs are safe, feasible, and promising for the treatment of patients with neurological diseases.
| S-EPMC6683773 | biostudies-literature
Project description:BackgroundCo-transplantation of bone marrow cells (BMCs) and mesenchymal stem cells (MSCs) is used as a strategy to improve the outcomes of bone marrow transplantation. Tonsil-derived MSCs (TMSCs) are a promising source of MSCs for co-transplantation. Previous studies have shown that TMSCs or conditioned media from TMSCs (TMSC-CM) enhance BMC engraftment. However, the factors in TMSCs that promote better engraftment have not yet been identified.MethodsMice were subjected to a myeloablative regimen of busulfan and cyclophosphamide, and the mRNA expression in the bone marrow was analyzed using an extracellular matrix (ECM) and adhesion molecule-targeted polymerase chain reaction (PCR) array. Nano-liquid chromatography with tandem mass spectrometry, real-time quantitative PCR, western blots, and enzyme-linked immunosorbent assays were used to compare the expression levels of metalloproteinase 3 (MMP3) in MSCs derived from various tissues, including the tonsils, bone marrow, adipose tissue, and umbilical cord. Recipient mice were conditioned with busulfan and cyclophosphamide, and BMCs, either as a sole population or with control or MMP3-knockdown TMSCs, were co-transplanted into these mice. The effects of TMSC-expressed MMP3 were investigated. Additionally, Enzchek collagenase and Transwell migration assays were used to confirm that the collagenase activity of TMSC-expressed MMP3 enhanced BMC migration.ResultsMice subjected to the myeloablative regimen exhibited increased mRNA expression of collagen type IV alpha 1/2 (Col4a1 and Col4a2). Among the various extracellular matrix-modulating proteins secreted by TMSCs, MMP3 was expressed at higher levels in TMSCs than in other MSCs. Mice co-transplanted with BMCs and control TMSCs exhibited a higher survival rate, weight recovery, and bone marrow cellularity compared with mice co-transplanted with BMCs and MMP3-knockdown TMSCs. Control TMSC-CM possessed higher collagenase activity against collagen IV than MMP3-knockdown TMSC-CM. TMSC-CM also accelerated BMC migration by degrading collagen IV in vitro.ConclusionsCollectively, these results indicate that TMSCs enhance BMC engraftment by the secretion of MMP3 for the modulation of the bone marrow extracellular matrix.
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Project description:UNLABELLED: Osteonecrosis after bone marrow transplantation is usually severe. Most patients develop acute and chronic graft-versus-host disease requiring a high dose of steroids for a long period of time. Generally ineffective nonoperative treatment in the past has resulted in treatment primarily with total hip arthroplasty (THA). We asked whether THA (1) reliably improved functional status, (2) led to more complications, and (3) THA after bone marrow transplantation was as durable as THA for idiopathic ON. We retrospectively reviewed 77 patients (123 hips) with osteonecrosis. The mean age at surgery was 33 years (range, 15.7-56 years). We performed all arthroplasties with an alumina ceramic bearing coupled with an alumina head 32 mm in diameter. The minimum followup was 2 years (mean, 9.2 years; range, 2-26 years). We documented seven revisions: three for late septic loosening, four for late aseptic loosening. Considering loosening of any component as the end point, the survivorship was 74.8% (range, 58.7%-90.9%) at 10 years. In this difficult situation, we believe the results acceptable. Septic loosening affecting this specific population has to be considered a serious event. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
| S-EPMC2505148 | biostudies-other
Project description: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-β/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.
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