RESUMEN
BACKGROUND AIMS: Cytopenias after allogeneic stem cell transplantation (allo-SCT) are a common complication, the underlying pathogenic mechanisms of which remain incompletely understood. Multipotent mesenchymal stromal/stem cell (MSC) therapy has been successfully employed in the treatment of immune-related disorders and can aid in the restoration of the hematopoietic niche. METHODS: A phase II clinical trial to assess the efficacy and safety of administering four sequential doses of ex-vivo expanded bone marrow MSCs from a third-party donor to patients with persistent severe cytopenias after allo-SCT was performed. RESULTS: The overall response rate on day 90 was 75% among the 27 evaluable patients (comprising 12 complete responses, 8 partial responses, and 7 with no response). The median time to respond was 14.5 days. Responses were observed across different profiles, including single or multiple affected lineages, primary or secondary timing, and potential immune-mediated or post-infectious pathophysiology versus idiopathic origin. With a median follow-up for surviving patients of 85 months after MSC infusion, 53% of patients are alive. Notably, no adverse events related to MSC therapy were reported. CONCLUSIONS: In summary, the sequential infusion of third-party MSCs emerges as a viable and safe therapeutic option, exhibiting potential benefits for patients experiencing cytopenias following allo-SCT.
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Trasplante de Células Madre Hematopoyéticas , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Trasplante Homólogo , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Adulto , Femenino , Trasplante de Células Madre Mesenquimatosas/métodos , Masculino , Persona de Mediana Edad , Células Madre Mesenquimatosas/citología , Trasplante Homólogo/métodos , Anciano , Resultado del Tratamiento , CitopeniaRESUMEN
BACKGROUND: Mesenchymal stromal cells (MSCs) are a promising option to treat knee osteoarthritis (OA). Their safety and usefulness have been reported in several short-term clinical trials but less information is available on the long-term effects of MSC in patients with osteoarthritis. We have evaluated patients included in our previous randomized clinical trial (CMM-ART, NCT02123368) to determine their long-term clinical effect. MATERIALS: A phase I/II multicenter randomized clinical trial with active control was conducted between 2012 and 2014. Thirty patients diagnosed with knee OA were randomly assigned to Control group, intraarticularly administered hyaluronic acid alone, or to two treatment groups, hyaluronic acid together with 10 × 106 or 100 × 106 cultured autologous bone marrow-derived MSCs (BM-MSCs), and followed up for 12 months. After a follow up of 4 years adverse effects and clinical evolution, assessed using VAS and WOMAC scorings are reported. RESULTS: No adverse effects were reported after BM-MSCs administration or during the follow-up. BM-MSCs-administered patients improved according to VAS, median value (IQR) for Control, Low-dose and High-dose groups changed from 5 (3, 7), 7 (5, 8) and 6 (4, 8) to 7 (6, 7), 2 (2, 5) and 3 (3, 4), respectively at the end of follow up (Low-dose vs Control group, p = 0.01; High-dose vs Control group, p = 0.004). Patients receiving BM-MSCs also improved clinically according to WOMAC. Control group showed an increase median value of 4 points (- 11;10) while Low-dose and High-dose groups exhibited values of - 18 (- 28;- 9) and - 10 (- 21;- 3) points, respectively (Low-dose vs Control group p = 0.043). No clinical differences between the BM-MSCs receiving groups were found. CONCLUSIONS: Single intraarticular injection of in vitro expanded autologous BM-MSCs is a safe and feasible procedure that results in long-term clinical and functional improvement of knee OA.
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Ácido Hialurónico/administración & dosificación , Ácido Hialurónico/uso terapéutico , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Osteoartritis de la Rodilla/terapia , Anciano , Femenino , Estudios de Seguimiento , Humanos , Ácido Hialurónico/efectos adversos , Inyecciones Intraarticulares , Masculino , Trasplante de Células Madre Mesenquimatosas/efectos adversos , Persona de Mediana Edad , Osteoartritis de la Rodilla/fisiopatología , Dolor/etiología , Dolor/fisiopatología , Trasplante Autólogo , Escala Visual AnalógicaRESUMEN
BACKGROUND: Chronic lower limb ischemia develops earlier and more frequently in patients with type 2 diabetes mellitus. Diabetes remains the main cause of lower-extremity non-traumatic amputations. Current medical treatment, based on antiplatelet therapy and statins, has demonstrated deficient improvement of the disease. In recent years, research has shown that it is possible to improve tissue perfusion through therapeutic angiogenesis. Both in animal models and humans, it has been shown that cell therapy can induce therapeutic angiogenesis, making mesenchymal stromal cell-based therapy one of the most promising therapeutic alternatives. The aim of this study is to evaluate the feasibility, safety, and efficacy of cell therapy based on mesenchymal stromal cells derived from adipose tissue intramuscular administration to patients with type 2 diabetes mellitus with critical limb ischemia and without possibility of revascularization. METHODS: A multicenter, randomized double-blind, placebo-controlled trial has been designed. Ninety eligible patients will be randomly assigned at a ratio 1:1:1 to one of the following: control group (n = 30), low-cell dose treatment group (n = 30), and high-cell dose treatment group (n = 30). Treatment will be administered in a single-dose way and patients will be followed for 12 months. Primary outcome (safety) will be evaluated by measuring the rate of adverse events within the study period. Secondary outcomes (efficacy) will be measured by assessing clinical, analytical, and imaging-test parameters. Tertiary outcome (quality of life) will be evaluated with SF-12 and VascuQol-6 scales. DISCUSSION: Chronic lower limb ischemia has limited therapeutic options and constitutes a public health problem in both developed and underdeveloped countries. Given that the current treatment is not established in daily clinical practice, it is essential to provide evidence-based data that allow taking a step forward in its clinical development. Also, the multidisciplinary coordination exercise needed to develop this clinical trial protocol will undoubtfully be useful to conduct academic clinical trials in the field of cell therapy in the near future. TRIAL REGISTRATION: ClinicalTrials.gov NCT04466007 . Registered on January 07, 2020. All items from the World Health Organization Trial Registration Data Set are included within the body of the protocol.
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COVID-19 , Diabetes Mellitus Tipo 2 , Trasplante de Células Madre Hematopoyéticas , Células Madre Mesenquimatosas , Noma , Tejido Adiposo , Animales , Ensayos Clínicos Fase II como Asunto , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/terapia , Método Doble Ciego , Humanos , Isquemia/diagnóstico , Isquemia/terapia , Estudios Multicéntricos como Asunto , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , SARS-CoV-2 , Resultado del TratamientoRESUMEN
BACKGROUND AIMS: The aim of this study was to compare prospectively the vasculogenic capacity of two cell sources, monocytes and CD133+ cells. METHODS: Cells were obtained from healthy donors by adherence or magnetic selection. Animals studies were performed in a model of hind limb ischemia and different groups were established according to type and number of cells infused. Revascularization was measured by sequential blood flow analysis using a laser Doppler device and by assessing capillary density in the ischemic muscles. In order to locate the infused cells, immunofluorescence and immunocytochemistry techniques were performed and analyzed by light and confocal microscopy. RESULTS: During the study period there was a significant improvement in both limb perfusion and capillary density in mice treated with either human monocytes or CD133+ cells (P<0.05) compared with non-treated mice. No cells were detected as incorporated into the vessels when 1 x 10(5) cells were used but with higher doses (1 x 10(6)) a few human cells were observed integrated into the vessels in both groups of treated mice. Supernatants of both cell types showed vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and platelet-derived growth factor- AB (PDGF-AB) expression. CONCLUSIONS: Treatment with human monocytes or CD133+ cells improves blood perfusion and capillary density in a murine model and both cell types seem to stimulate vasculogenesis in a fairly similar way.
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Antígenos CD/metabolismo , Glicoproteínas/metabolismo , Miembro Posterior/irrigación sanguínea , Miembro Posterior/patología , Isquemia/patología , Monocitos/citología , Neovascularización Fisiológica , Péptidos/metabolismo , Antígeno AC133 , Inductores de la Angiogénesis/metabolismo , Animales , Capilares/patología , Movimiento Celular , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunofenotipificación , Flujometría por Láser-Doppler , Ratones , Microscopía Confocal , Músculos/patología , Perfusión , Fenotipo , Flujo Sanguíneo Regional , Coloración y EtiquetadoRESUMEN
BACKGROUND AND OBJECTIVES: Whether human mesenchymal stem cells (MSC) can be transplanted is controversial and their presence in peripheral blood is not fully accepted. In the present study we have analyzed whether, within the allogeneic transplantation setting, MSC are of host or donor origin. DESIGN AND METHODS: Bone marrow MSC from 19 patients who had undergone allogeneic transplantation were expanded and identified using immunophenotypic markers. After that, chimerism studies were performed using reverse transcription polymerase chain reaction of short tandem repeat (STR) loci. Analyses were carried out at different time-points after transplantation, with a total of 44 samples studied. Bone marrow was used as the source of stem cells for transplantation in 4 cases and peripheral blood in 15 cases. The conditioning regimen was standard in 9 patients and non-myeloablative in 10 patients. RESULTS: Our results show that in the great majority of cases analyzed (17 out 19), MSC were of host origin. However, in 2 patients with multiple myeloma who had received a reduced intensity transplantation using peripheral blood stem cells, MSC were partially of donor origin (60.17% and 26.13% of total MSC). INTERPRETATION AND CONCLUSIONS: These findings indicate that after allogeneic transplantation MSC from the donor can engraft in bone marrow. Moreover, since the stem cells were obtained from peripheral blood, it can be concluded that MSC circulate among mobilized peripheral blood stem cells and can engraft in bone marrow after allogeneic transplantation.