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1.
Lancet Haematol ; 7(2): e134-e145, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31704264

RESUMO

BACKGROUND: Benefits of cord blood transplantation include low rates of relapse and chronic graft-versus-host disease (GVHD). However, the use of cord blood is rapidly declining because of the high incidence of infections, severe acute GVHD, and transplant-related mortality. UM171, a haematopoietic stem cell self-renewal agonist, has been shown to expand cord blood stem cells and enhance multilineage blood cell reconstitution in mice. We aimed to investigate the safety and feasibility of single UM171-expanded cord blood transplantation in patients with haematological malignancies who do not have a suitable HLA-matched donor. METHODS: This single-arm, open-label, phase 1-2 safety and feasibility study was done at two hospitals in Canada. The study had two parts. In part 1, patients received two cord blood units (one expanded with UM171 and one unmanipulated cord blood) until UM171-expanded cord blood demonstrated engraftment. Once engraftment was documented we initiated part 2, reported here, in which patients received a single UM171-expanded cord blood unit with a dose de-escalation design to determine the minimal cord blood unit cell dose that achieved prompt engraftment. Eligible patients were aged 3-64 years, weighed 12 kg or more, had a haematological malignancy with an indication for allogeneic hematopoietic stem cell transplant and did not have a suitable HLA-matched donor, and a had a Karnofsky performance status score of 70% or more. Five clinical sites were planned to participate in the study; however, only two study sites opened, both of which only treated adult patients, thus no paediatric patients (aged <18 years) were recruited. Patients aged younger than 50 years without comorbidities received a myeloablative conditioning regimen (cyclophosphamide 120 mg/kg, fludarabine 75 mg/m2, and 12 Gy total body irradiation) and patients aged older than 50 years and those with comorbidities received a less myeloablative conditioning regimen (cyclophosphamide 50 mg/kg, thiotepa 10 mg/kg, fludarabine 150 mg/m2, and 4 Gy total body irradiation). Patients were infused with the 7-day UM171-expanded CD34-positive cells and the lymphocyte-containing CD34-negative fraction. The primary endpoints were feasibility of UM171 expansion, safety of the transplant, kinetics of hematopoietic reconstitution (time to neutrophil and platelet engraftment) of UM171-expanded cord blood, and minimal pre-expansion cord blood unit cell dose that achieved prompt engraftment. We analysed feasibility in all enrolled patients and all other primary outcomes were analysed per protocol, in all patients who received single UM171-expanded cord blood transplantation. This trial has been completed and was registered with ClinicalTrials.gov, NCT02668315. FINDINGS: Between Feb 17, 2016, and Nov 11, 2018, we enrolled 27 patients, four of whom received two cord blood units for safety purposes in part 1 of the study. 23 patients were subsequently enrolled in part 2 to receive a single UM171-expanded cord blood transplant and 22 patients received a single UM171-expanded cord blood transplantation. At data cutoff (Dec 31, 2018), median follow-up was 18 months (IQR 12-22). The minimal cord blood unit cell dose at thaw that achieved prompt engraftment as a single cord transplant after UM171 expansion was 0·52 × 105 CD34-positive cells. We successfully expanded 26 (96%) of 27 cord blood units with UM171. Among the 22 patients who received single UM171-expanded cord blood transplantation, median time to engraftment of 100 neutrophils per µL was 9·5 days (IQR 8-12), median time to engraftment of 500 neutrophils per µL was 18 days (12·5-20·0), and no graft failure occurred. Median time to platelet recovery was 42 days (IQR 35-47). The most common non-haematological adverse events were grade 3 febrile neutropenia (16 [73%] of 22 patients) and bacteraemia (nine [41%]). No unexpected adverse events were observed. One (5%) of 22 patients died due to treatment-related diffuse alveolar haemorrhage. INTERPRETATION: Our preliminary findings suggest that UM171 cord blood stem cell expansion is feasible, safe, and allows for the use of small single cords without compromising engraftment. UM171-expanded cord blood might have the potential to overcome the disadvantages of other cord blood transplants while maintaining the benefits of low risk of chronic GVHD and relapse, and warrants further investigation in randomised trials. FUNDING: Canadian Institutes of Health Research, Canadian Cancer Society and Stem Cell Network.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Indóis/farmacologia , Pirimidinas/farmacologia , Adolescente , Adulto , Autorrenovação Celular/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/transplante , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Intervalo Livre de Doença , Estudos de Viabilidade , Neutropenia Febril/etiologia , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Células-Tronco Hematopoéticas/citologia , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Resultado do Tratamento , Adulto Jovem
2.
Exp Hematol ; 80: 11-15, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31786243

RESUMO

Umbilical cord blood transplant is an alternative graft source for patients lacking a human leukocyte antigen-matched donor; however, delayed engraftment times have historically resulted in transplant-related morbidity and mortality from complications such as infections and ineffective hematopoiesis. Recent advances in ex vivo expansion techniques have successfully augmented the initial cell dose delivered from an umbilical cord blood graft, leading to improved immune reconstitution, durable hematopoiesis, decreased transplant-related morbidity and mortality, and better outcomes. Herein we review the data for existing and developing ex vivo expansion techniques, with a focus on the preclinical and clinical data for nicotinamide-mediated cord blood expansion across both malignant and benign hematologic indications.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Sangue Fetal/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Niacinamida/farmacologia , Aloenxertos , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Ensaios Clínicos como Assunto/métodos , Previsões , Neoplasias Hematológicas/terapia , Células-Tronco Hematopoéticas/citologia , Humanos , Recém-Nascido , Estudos Multicêntricos como Assunto , Niacinamida/análogos & derivados
3.
Exp Hematol ; 80: 21-26, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31734258

RESUMO

Umbilical cord blood CD34+ (UCB-CD34+) stem cells are clinically used in hematopoietic cell transplantation. However, there are limitations in the use of umbilical cord blood transplants because of the small number of cells and delayed engraftment. To gain a better understanding of functional components of UCB, we have detected and characterized CD34+ microparticles (CD34+MPs) from cord blood units. We collected cord blood units and assessed the numbers of CD34+MPs before and after red blood cell and plasma depletion by SEPAX processing using flow cytometry analysis. In parallel we identified MPs by electron microscopy. CD34+MPs and cells were isolated by MACs sorting. MicroRNAs (miR-106, miR-221, miR-517, miR-519, and miR-221) exhibited a characteristic microRNA profile that was further validated in isolated CD34+MPs. We found that in cord blood, there are CD34+MPs that carry microRNAs.


Assuntos
Micropartículas Derivadas de Células , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Sangue Fetal/química , Células-Tronco Hematopoéticas/química , MicroRNAs/sangue , Anexina A5/análise , Antígenos CD34/análise , Micropartículas Derivadas de Células/química , Células-Tronco Hematopoéticas/ultraestrutura , Humanos , Recém-Nascido , MicroRNAs/isolamento & purificação , Microscopia Eletrônica , Reação em Cadeia da Polimerase em Tempo Real
4.
Transplant Proc ; 51(9): 3155-3158, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31611125

RESUMO

We present a case report of a boy diagnosed with both chronic granulomatous disease (CGD) and familial celiac disease (CD) who underwent cord blood transplantation from a partially matched sibling donor. The presentation of CD resembled Crohn-like enteropathy, which is a canonical manifestation of CGD. Nearly 1 year post-hematopoietic stem cell transplantation (HSCT), a gluten-containing diet was reintroduced, and no reappearance of clinical, serologic, or histologic markers of CD was observed. The relatively high incidence of rare genetic diseases in pediatric patients suggests the need for additional caution in the interpretation of symptoms mimicking already known hallmarks of more common conditions. In addition, the presented data confirm the previous rare observations that allogeneic HSCT leads to durable induction of gluten tolerance in patients with CD, which can warrant its use in patients with refractory subtypes of CD.


Assuntos
Doença Celíaca/complicações , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/cirurgia , Doença Celíaca/genética , Criança , Pré-Escolar , Doença Granulomatosa Crônica/genética , Humanos , Lactente , Masculino , Irmãos , Transplante Homólogo
5.
Blood ; 134(12): 924-934, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31292117

RESUMO

Allogeneic hematopoietic cell transplantation involves consideration of both donor and recipient characteristics to guide the selection of a suitable graft. Sufficient high-resolution donor-recipient HLA match is of primary importance in transplantation with adult unrelated donors, using conventional graft-versus-host disease prophylaxis. In cord blood transplantation, optimal unit selection requires consideration of unit quality, cell dose and HLA-match. In this summary, the National Marrow Donor Program (NMDP) and the Center for International Blood and Marrow Transplant Research, jointly with the NMDP Histocompatibility Advisory Group, provide evidence-based guidelines for optimal selection of unrelated donors and cord blood units.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/normas , Seleção do Doador/normas , Sangue Fetal , Transplante de Células-Tronco Hematopoéticas/normas , Doadores não Relacionados , Adulto , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Seleção do Doador/métodos , Sangue Fetal/imunologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade/métodos , Teste de Histocompatibilidade/normas , Humanos , Recém-Nascido , Sistema de Registros , Doadores não Relacionados/provisão & distribução
6.
Life Sci ; 232: 116632, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31278944

RESUMO

AIMS: The inflammation modulation effects of mesenchymal stromal cell-derived exosomes (MSC-EXO) are well established. We aimed to explore the mechanism behind the inflammatory responses of numerous exosomal cargo molecules that have been neglected in molecular biology research, and to develop an exosomal cargo delivery system that can exert a stronger therapeutic effect on myocardial ischemia-reperfusion (I/R) injury. MAIN METHODS: Computational approaches were used to identify key exosomal miRNAs and their downstream mRNAs that are expressed in the inflammatory response. Direct interactions between miRNA-181a and the c-Fos mRNA complex were confirmed by luciferase reporter assay. MSC-EXO carrying miRNA-181a-overexpressing lentiviruses were intramyocardially injected into a mouse model of myocardial I/R injury. I/R progression was evaluated through echocardiography and immunofluorescence microscopy. KEY FINDINGS: miRNA-181a provided substantial coverage against a host of immune-related genes through the miRNA-mRNA network. miRNA-181a delivery by MSC-EXO combined the immune-suppressing effect of miRNA-181a and the cell targeting capability of MSC-EXO to exert a stronger therapeutic effect on myocardium I/R injury. SIGNIFICANCE: We showed the potential of MSC-EXO as a tool for the specific delivery of small RNAs in vivo. This study shed new light on the potential application of miRNA-181a-overexpressing MSC-EXO as a therapeutic strategy for myocardial I/R injury.


Assuntos
Células-Tronco Mesenquimais/metabolismo , MicroRNAs/sangue , Traumatismo por Reperfusão Miocárdica/metabolismo , Animais , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Exossomos , Humanos , Inflamação/terapia , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo
7.
Eur J Haematol ; 103(3): 172-177, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177565

RESUMO

OBJECTIVES: Umbilical cord blood transplantation (UCBT) and haploidentical hematopoietic stem cell transplantation (haplo-HSCT) modalities have been developed to offset the lack of matched donors. In this study, we compare the transfusion requirements of patients undergoing UCBT and haplo-HSCT in a single institution with the aim of providing additional information for clinicians to choose the most adequate alternative graft for HSCT. METHODS: The study reviewed 67 and 46 patients undergoing UCBT and haplo-HSCT, respectively. RESULTS: There were no significant differences for RBC and PLT requirements according to the transplantation modality. Median time to RBC transfusion independence was 35 and 25.5 days in patients who received an UCBT and haplo-HSCT, respectively (P = 0.38), while median time to platelet transfusion independence was 31 days for UCBT patients and 23 for haplo-HSCT patients (P < 0.001). Days until neutrophils > 0.5 × 109 /L were the only variable that significantly influenced RBC and PLT requirements for both transplantation modalities. Cumulative incidence of RBC and PLT transfusion independence at 90 days after transplantation was similar for both UCBT and haplo-HSCT. CONCLUSIONS: Both transplantation platforms require prolonged and intensive supportive RBC and PLT transfusion therapy. Both transplantation platforms require prolonged and intensive supportive RBC and PLT transfusion therapy.


Assuntos
Transfusão de Sangue , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Transplante Haploidêntico , Adolescente , Adulto , Idoso , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Feminino , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
8.
Int J Hematol ; 110(1): 39-49, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31152417

RESUMO

Cord blood (CB) has been an alternative stem cell source for patients with a wide variety of hematological diseases. Cord blood confers the advantages of rapid availability and higher tolerance to two HLA antigen mismatches compared with unrelated donors, and this has increased opportunities for patients who do not have suitable donors or require urgent transplantation. Although the higher rate of engraftment failure remains a serious concern after cord blood transplantation (CBT), the mechanisms underlying this risk have gradually been clarified, which has helped to improve engraftment. Recent studies of CBT and other alternatives have reported comparable outcomes. Moreover, CBT shows promise even when patients are in a non-remission status, which may reflect the potent graft-versus-leukemia effect of CB. Here we compare the most recent outcomes of CBT with those of other stem cell sources and discuss the potential of CB and several outstanding issues that require resolution.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/tendências , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/normas , Efeito Enxerto vs Leucemia , Doenças Hematológicas/terapia , Histocompatibilidade , Humanos , Japão
9.
Int J Hematol ; 110(1): 50-58, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31123927

RESUMO

In patients with hematologic malignancies, the outcome of umbilical cord blood transplantation has improved and is now comparable to that of matched unrelated donor transplantation. However, the limitation of using umbilical cord blood has been a delay in both hematopoietic and immunologic recovery. Strategies have been proposed to overcome these limitations. One strategy involves ex vivo expansion of the umbilical cord blood unit prior to transplantation. A second strategy involves exposure of the umbilical cord blood graft to compounds aimed at improving homing and engraftment following transplantation. Many of these strategies are now being tested in late phase multi-center clinical trials. If proven cost effective and efficacious, they may alter the landscape of donor options for allogeneic stem cell transplantation.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Sangue Fetal/citologia , Ensaios Clínicos como Assunto , Sangue Fetal/imunologia , Neoplasias Hematológicas/terapia , Humanos , Transplante Homólogo
10.
Pediatr Int ; 61(6): 566-571, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30974480

RESUMO

BACKGROUND: The prognosis of high-risk neuroblastoma stage 4 with bone marrow metastasis, MYCN amplified, or refractory neuroblastoma is poor. To date, no standard treatment has been established. In four selected cases, we challenged the killer-cell immunoglobulin-like receptor ligand mismatch cord blood transplantation in graft-versus-host disease (GVHD) with reduced-intensity conditioning. METHODS: Prior to this study, conventional chemotherapy, autologous peripheral blood stem cell transplantation with high-dose chemotherapy (busulfan and melphalan), surgery and radiation therapy were completed in every case. The status before cord blood transplantation in two cases was not complete remission (CR) and in the others it was CR. The primary site was the mediastinum, two adrenal glands and a retroperitoneum, respectively. Three patients had bone and bone marrow metastasis and one had MYCN amplification. In all cases, international neuroblastoma pathology classification was unfavorable histology. All patients were >2 years of age. RESULTS: Relapse occurred only in one patient 17 months after the last transplantation, and the other three patients maintained disease-free survival for 74, 36, and 24 months, respectively. In one case of relapse the disease could be controlled by conventional chemotherapy. Except one, all patients had no severe complications, such as acute or chronic GVHD. One patient had gastric antral vascular ectasia and hemorrhagic cystitis. CONCLUSION: This strategy might be feasible and should be investigated for efficacy in the future. No definite conclusion can be made, however, due to the very small number of patients. Further prospective studies are required to determine its efficacy.


Assuntos
Neoplasias das Glândulas Suprarrenais/terapia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Neoplasias do Mediastino/terapia , Neuroblastoma/terapia , Receptores KIR/imunologia , Neoplasias Retroperitoneais/terapia , Neoplasias das Glândulas Suprarrenais/imunologia , Neoplasias das Glândulas Suprarrenais/patologia , Biomarcadores , Pré-Escolar , Feminino , Humanos , Ligantes , Masculino , Neoplasias do Mediastino/imunologia , Neoplasias do Mediastino/patologia , Neuroblastoma/imunologia , Neuroblastoma/patologia , Neoplasias Retroperitoneais/imunologia , Neoplasias Retroperitoneais/patologia
11.
Blood Cancer J ; 9(4): 46, 2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30979868

RESUMO

The role of umbilical cord blood transplantation (CBT) in acute myeloid leukemia (AML) patients with active disease at allogeneic hematopoietic cell transplantation (allo-HCT) remains poorly investigated. In this study, we compared transplantation outcomes of 2963 patients with primary refractory or relapsed AML given CBT, 10/10 HLA-matched UD, or 9/10 HLA-matched UD allo-HCT from 2004 to 2015 at EBMT-affiliated centers. Neutrophil engraftment and complete remission rates in CBT, UD 10/10, and UD 9/10 recipients were 75 and 48%, 93 and 69%, and 93 and 70%, respectively. In multivariate Cox analyses, in comparison with CBT (n = 285), UD 10/10 recipients (n = 2001) had a lower incidence of relapse (HR = 0.7, P = 0.001), a lower incidence of non relapse mortality (HR = 0.6, P < 0.001), better GVHD-free and leukemia-free survival (GRFS, HR = 0.8, P < 0.001) and better survival (HR = 0.6, P < 0.001). Further, in comparison with CBT, 9/10 UD recipients (n = 677) also had a lower incidence of relapse (HR = 0.8, P = 0.02), a lower incidence of nonrelapse mortality (HR = 0.7, P = 0.008), better GRFS (HR = 0.8, P = 0.01) and better survival (HR = 0.7, P < 0.001). In summary, these data suggest that in AML patients with active disease at transplantation, allo-HCT with UD results in better transplantation outcomes than CBT.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Doadores não Relacionados , Adulto Jovem
12.
Int J Hematol ; 110(1): 119-123, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30879266

RESUMO

A 42-year-old female complaining of fever and night sweats was diagnosed with acute megakaryoblastic blast phase chronic myeloid leukemia (CML-BP). She had massive splenomegaly, left pleural effusion with leukemia infiltration, and moderate myelofibrosis. She received dasatinib monotherapy (140 mg/day) as for induction, after which her pleural effusion rapidly resolved and hematological remission was achieved. However, CML relapsed 4 months after starting dasatinib due to increased BCR-ABL fusion signals in the peripheral blood. The T315I mutation was also detected at the recurrence of CML. As a salvage treatment, ponatinib monotherapy (45 mg/day) was started immediately. After 5 months, BCR-ABL fusion signals decreased to 5%, and myelofibrosis improved from MF Grade 2 to 1; she then underwent allogeneic bone marrow transplantation from an unrelated donor. However, the graft failed, and cord blood transplantation (CBT) was performed. Ponatinib (15 mg/day) was continued after CBT as a maintenance treatment, with molecular complete response continuing for more than 1 year with no severe adverse events, including cardiovascular events. There is limited evidence regarding the optimal dose and schedule of ponatinib before and after allogeneic hematopoietic stem cell transplantation, especially in patients with CML-BP having T315I mutation; thus, well-designed clinical trials are warranted.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Imidazóis/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Mutação , Piridazinas/uso terapêutico , Adulto , Crise Blástica/patologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Células Progenitoras de Megacariócitos/patologia , Recidiva , Terapia de Salvação/métodos , Transplante Homólogo , Resultado do Tratamento
13.
Blood Cancer J ; 9(3): 31, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30842405

RESUMO

Allogeneic hematopoietic stem cell transplantation is the sole curative therapy for myelodysplastic syndrome (MDS). However, there is concern regarding graft failure and relapse in patients who undergo cord blood transplantation (CBT). We conducted a retrospective study of the CBT outcomes in MDS patients using the Japanese Data Center for Hematopoietic Cell Transplantation database. Seven hundred fifty-two de novo MDS patients of ≥18 years of age (median, 58 years) undergoing their first CBT between 2001 and 2015 were examined. Two-thirds of the patients were male, and were RAEB. The cumulative incidences of neutrophil and platelet engraftment at day 100 were 77 and 59%, respectively. The 3-year overall survival (OS) was 41% and the median survival of the patients was 1.25 years. A multivariate analysis of pre-transplant variables showed that the age, gender, cytogenetic subgroups, number of RBC transfusions, HCT-CI and year of CBT significantly influenced the outcome. The cumulative incidence of acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) was 32 and 21%, respectively. A survival benefit was observed in patients who developed cGVHD, but not aGVHD. Our results suggest that CBT is an acceptable alternative graft and that a graft-versus-MDS effect can be expected, especially in patients who develop cGVHD.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Síndromes Mielodisplásicas/complicações , Adulto , Idoso , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/diagnóstico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/terapia , Prognóstico , Análise de Sobrevida , Transplante Homólogo
14.
Eur J Med Res ; 24(1): 10, 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30736851

RESUMO

OBJECTIVE: Difficulty in wound healing is one common complication of diabetes mellitus. The study explored whether the therapeutic effect of human umbilical cord mesenchymal stem cells (hUCMSCs) on diabetic ulcer wound was enhanced by the activation of the Wnt signaling pathway. METHODS: Rat diabetic model was established by intraperitoneal injection of Streptozotocin (STZ). hUCMSCs were purified and seeded on the collagen-chitosan laser drilling acellular dermal matrix (CCLDADM) scaffold, which was subsequently implanted into the cutaneous wound of normal and diabetic rats, followed by daily injection of Wnt signaling pathway agonist (Wnt3a) or antagonist (sFRP3) at the edge of the scaffold. Wound healing was checked on days 7, 14, and 21, and the fibrous tissue deposition, capillaries, and epidermal regeneration at the wound were examined by hematoxylin-eosin staining. The hUCMSCs-CCLDADM scaffold was cultured in vitro and treated with Wnt3a or sFRP3, followed by evaluation of cell proliferation, cell proliferation rate, survival status, and altered protein levels in the Wnt signaling pathway using BrdU staining, CCK-8 assay, live/dead staining, and Western blotting, respectively. RESULTS: On days 7 and 14 postoperatively, the speed of wound healing was significantly lower in diabetic rats than that in normal control rats. This phenomenon was significantly improved by the activation of the Wnt signaling pathway that also elevated the fibrous protein deposition and the abundance of capillary in the granulation tissue. Conversely, blockade of Wnt signaling slowed the healing of skin wound in diabetic rats. The activation of Wnt signaling pathway promoted the proliferation and differentiation and decreased the apoptosis of hUCMSCs, thereby elevating the number of living hUCMSCs on the CCLDADM scaffold, while the suppression exerted a contrary effect. CONCLUSION: The activation of the Wnt signaling pathway promotes the healing of diabetic skin wound by the regulation of proliferation and differentiation of hUCMSCs on the CCLDADM scaffold.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Diabetes Mellitus Experimental , Transplante de Células-Tronco Mesenquimais/métodos , Via de Sinalização Wnt/fisiologia , Cicatrização/fisiologia , Animais , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Xenoenxertos , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
15.
Biomed Pharmacother ; 111: 624-630, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30611986

RESUMO

BACKGROUND: The transplantation of stem cells is effective in the treatment of acute myocardial infarction (AMI). But the mechanisms of stem cell transplantation for the treatment of AMI have not been clearly confirmed. This article is to compare cardiac function, myocardial fibrosis, inflammatory cell infiltration, apoptotic index, and M1 macrophage to M2 macrophage ratios 4 weeks after hUCB-MSCs transplantation in Mice with AMI. METHODS: Mice model of AMI was divided into two groups randomly. Human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) were transplanted to the intervention group via mice tail vein, and saline solution was used for the control group. Masson staining calculated the proportion of the remaining myocardium and collagen volume fraction (CVF) in the infarct area, flow cytometry and immunofluorescence staining to analyze M1 / M2 subtype and its ratio were performed. Serum IL-6 and galectin-3 levels were determined using ELISA. RESULTS: The results showed that heart function of the intervention group was significantly better than that of the control group, and the degree of fibrosis and inflammation in the intervention group were lower than those in the control group. The ratio of monocyte M1/M2 in peripheral blood, spleen and myocardial tissue in hUCB-MSCs transplantation was significantly lower than that of the control group. But there is no significant difference in the apoptotic index between two groups. The ELISA results showed that serum IL-6 (97.98 ± 5.94 pg/ml) and galectin-3 levels (69.94 ± 5.11 ng/ml) were lower in the intervention group than in the control group (IL-6: 118.2 ± 5.03 pg/ml; galectin-3: 83.14 ± 2.76 ng / ml). However, compared with the control group, only IL-6 showed a significant decrease in the intervention group (p = 0.032). CONCLUSION: Intravenous transplantation of hUCB-MSCs can reduce inflammatory response by stimulating the conversion of intracardiac and extracardiac macrophage subtype M1 / M2, decrease the serum IL-6 and galectin-3 levels, improve cardiac function and protect the infarcted myocardium.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Macrófagos/fisiologia , Transplante de Células-Tronco Mesenquimais/métodos , Monócitos/fisiologia , Infarto do Miocárdio/terapia , Administração Intravenosa , Animais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Infarto do Miocárdio/sangue , Infarto do Miocárdio/patologia , Distribuição Aleatória
16.
Metabolism ; 95: 93-101, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30668962

RESUMO

OBJECTIVE: Senile osteoporosis is one of the most common age-related diseases worldwide. Accumulating evidences have indicated that young blood can reverse age-related impairments. Extracellular vesicles (EVs) exert therapeutic effects in a variety of diseases by delivering bioactive molecules such as microRNAs (miRNAs). The aim of the study is to evaluate the therapeutic potential of EVs from human umbilical cord blood plasma (UCB-EVs) on senile osteoporosis and to preliminarily clarify the underlying mechanism. METHODS: UCB-EVs were injected into the tail vein of aged (16 months old) male C57BL/6 mice. Microcomputed tomography was performed to evaluate bone mass and microarchitecture of mice. The osteogenic and osteoclastic activities were determined by quantitative real-time PCR (qRT-PCR), histological examination and western blot analysis. In vitro, qRT-PCR assay was undertaken to explore the enrichment levels of a number of miRNAs that have positive effects in reducing bone loss. The efficacy of UCB-EVs on osteoblastic differentiation of bone marrow mesenchymal stromal cells (BMSCs) and osteoclastogenesis of RAW264.7 cells were assessed by cytochemical staining. Gene and protein expression changes were detected by qRT-PCR and western blotting respectively. Meanwhile, the roles of the selected miRNA in the regulatory effects of UCB-EVs on BMSCs and RAW264.7 cells were evaluated by using specific miRNA inhibitor. RESULTS: The intravenous injection of UCB-EVs for two months attenuated bone loss in old mice, as defined by increased trabecular and cortical bone mass, enhanced osteoblast formation and reduced osteoclast formation compared to the control mice. In vitro, UCB-EVs could promote the osteogenic differentiation of BMSCs and inhibit the osteoclastogenesis of RAW264.7 cells. Moreover, it was confirmed that miR-3960 was highly enriched in UCB-EVs and miR-3960 inhibitor reversed the stimulatory effect of UCB-EVs on osteoblastic differentiation of BMSCs. CONCLUSION: Our findings indicate that UCB-EVs ameliorate age-related bone loss by stimulating bone formation and inhibiting bone resorption, and miR-3960 mediated the osteogenic effect of UCB-EVs on BMSCs. Thus, UCB-EVs may represent a promising agent for prevention of senile osteoporosis.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Vesículas Citoplasmáticas/transplante , Vesículas Extracelulares/metabolismo , Osteoporose/terapia , Animais , Diferenciação Celular , Humanos , Masculino , Células-Tronco Mesenquimais , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/uso terapêutico , Osteoblastos , Osteoporose/diagnóstico por imagem , Plasma , Células RAW 264.7 , Microtomografia por Raio-X
17.
Behav Brain Res ; 362: 56-63, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30639506

RESUMO

Current treatment options for hypoxic-ischemic encephalopathy (HIE) are limited. Human umbilical cord mesenchymal stem cells (UC-MSCs) and cord blood mononuclear cells (CB-MNCs) offer great potential for the treatment of many neurological diseases. The aim of the present study was to identify which cell type is more effective for the treatment of HIE. PKH26-labeled UC-MSCs and CB-MNCs were transplanted into rats with hypoxia-ischemia (HI)-induced brain damage. Apoptotic cell numbers in the brain, as labeled by TUNEL, were assessed. Myelination and gliosis were investigated using myelin basic protein and glial fibrillary acidic protein immunohistochemistry, respectively. The Morris water maze was used to assess animal learning abilities. Our data show that transplantation of UC-MSCs or CB-MNCs after HI reduced astrogliosis, prevented neuronal loss in the striatum, and markedly improved functional brain outcomes after a 28-day recovery period. Moreover, treatment with CB-MNCs increased the proportion of mature oligodendrocytes and improved myelination in cortical areas. Both UC-MSCs and CB-MNCs may result in the recovery of neurological function in HI rats. Based on our data, UC-MSCs and UCB-MNCs may be particularly effective stem cell subsets for treatment of neonatal HIE.


Assuntos
Hipóxia-Isquemia Encefálica/terapia , Memória/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Cordão Umbilical/citologia , Animais , Animais Recém-Nascidos , Diferenciação Celular/fisiologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Modelos Animais de Doenças , Transplante de Células-Tronco Mesenquimais/métodos , Ratos
18.
Brain Dev ; 41(2): 173-181, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30177297

RESUMO

Perinatal brain injury can cause death in the neonatal period and lifelong neurodevelopmental deficits. Stem cell transplantation had been proved to be effective approach to ameliorate neurological deficits after brain damage. In this study we examine the effect of human umbilical cord blood CD34+ cells on model of neonatal rat hypoxic-ischemic brain damage and compared the neuroprotection of transplantation of CD34+ cells to mononuclear cells from which CD34+ cells isolated on neonatal hypoxic-ischemia rat model. Seven-day-old Sprague-Dawley rats were subjected to hypoxic-ischemic (HI) injury, CD34+ cells (1.5 × 104 cells) or mononuclear cells (1.0 × 106 cells) were transplanted into mice by tail vein on the 7 day after HI. The transplantation of CD34+ cells significantly improved motor function of rat, and reduced cerebral atrophy, inhibited the expression of glial fibrillary acidic protein (GFAP) and apoptosis-related genes: TNF-α, TNFR1, TNFR2, CD40, Fas, and decreased the activation of Nuclear factor kappa B (NF-κB) in damaged brain. CD34+ cells treatment increased the expression of DCX and lectin in ipsilateral brain. Moreover, the transplantation of CD34+ cells and MNCs which were obtained from the same amount of human umbilical cord blood had similar effects on HI. Our data demonstrated that transplantation of human umbilical cord blood CD34+ cells can ameliorate the neural functional defect and reduce apoptosis and promote nerve and vascular regeneration in rat brain after HI injury and the effects of transplantation of CD34+ cells were comparable to that of MNCs in neonatal hypoxic-ischemia rat model.


Assuntos
Antígenos CD34 , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Hipóxia-Isquemia Encefálica/terapia , Animais , Animais Recém-Nascidos , Antígenos CD34/isolamento & purificação , Modelos Animais de Doenças , Encefalite/complicações , Encefalite/prevenção & controle , Humanos , Hipóxia-Isquemia Encefálica/complicações , Ratos Sprague-Dawley
19.
Exp Clin Transplant ; 17(2): 251-258, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30346265

RESUMO

OBJECTIVES: Liver transplantation is the well-known treatment for chronic liver diseases; however, postoperative complications and lack of donors continue to be limitations with this treatment. Investigating new modalities for treatment of chronic liver illness is a must. In the present study, we aimed to clarify the effects of an in vitro hepatocyte-differentiated human unrestricted somatic stem cell transplant as a new cell-based therapy in an experimental model of chronic liver failure. MATERIALS AND METHODS: Human umbilical cord blood-derived unrestricted somatic stem cells were isolated, cultured, propagated, and characterized. Cells were directed to differentiate into hepatocyte-like cells. An animal model of carbon tetrachloride cirrhotic liver failure was prepared, and the human in vitro differentiated unrestricted somatic stem cells were transplanted into the experimental model. Animals that did not receive transplant served as the pathologic control group. Animals were euthanized 12 weeks after transplant, and liver functions and histopathology were assessed. RESULTS: Compared with the pathologic control group, the transplant group showed improvements in levels of alanine aminotransferase, aspartate aminotransferase, albumin, and bilirubin. Histopathologic examination of the transplant group also showed improvements in hydropic degeneration and fibrosis. CONCLUSIONS: The use of unrestricted somatic stem cells, isolated and propagated from cord blood and then differentiated into hepatocyte-like cells, improved both fibrosis and normal function of cirrhotic livers. These cells could be considered as a line of cell-based therapy in cases of chronic liver disease.


Assuntos
Células-Tronco Adultas/transplante , Doença Hepática Induzida por Substâncias e Drogas/cirurgia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Sangue Fetal/citologia , Hepatócitos/transplante , Cirrose Hepática Experimental/cirurgia , Regeneração Hepática , Fígado/patologia , Células-Tronco Adultas/metabolismo , Animais , Biomarcadores/metabolismo , Tetracloreto de Carbono , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Camundongos Endogâmicos BALB C , Fenótipo , Fatores de Tempo
20.
Int J Hematol ; 109(1): 115-124, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30302739

RESUMO

Hospital readmissions have been used as a prognostic indicator for patients receiving allogeneic hematopoietic cell transplantation (HCT). However, the impact of readmission during early and mid-phase of cord blood transplantation (CBT) on long-term outcomes has not been fully investigated. We retrospectively analyzed 156 adult patients who received single-unit CBT in our institute. Among this cohort, thirteen patients (8%) were readmitted within 30 days after discharge, and 27 (17%) were readmitted within 90 days after discharge. The most common causes for readmission within 30 and 90 days of discharge were infection, chronic graft-versus-host disease, and relapse. Higher cryopreserved cord blood CD34+ cell count was only significantly associated with lower readmission within 90 days after discharge. The probabilities of overall survival were significantly lower in patients readmitted within 90 days after discharge compared with those who were not readmitted within 90 days after discharge in univariate and multivariate analysis. These data suggest that readmission within 90 days after discharge may have a significant impact on long-term mortality after single-unit CBT.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Readmissão do Paciente , Adulto , Feminino , Doença Enxerto-Hospedeiro , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Fatores de Tempo
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