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1.
Stem Cell Res Ther ; 10(1): 363, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791397

RESUMO

BACKGROUND: Diabetic nephropathy (DN) is one of the most severe chronic diabetic complications and the main cause of end-stage renal disease. Chronic inflammation plays a key role in the development of DN. However, few treatment strategies are available; therefore, new and effective strategies to ameliorate DN at the early stage must be identified. METHODS: Mesenchymal stem cells (MSCs) are characterized by anti-inflammatory and immune regulatory abilities. We developed a rhesus macaque model of DN and administered MSCs four times over 2 months. We measured blood glucose level, HbA1c, and levels of renal function parameters in the blood and urine, and cytokine levels in the kidney and blood circulatory system of rhesus macaques. Also, we analyzed the renal pathological changes of rhesus macaques. In vitro, we treated tubular epithelial cells (HK2) with 30 mmol/L glucose and 10 ng/mL human recombinant TNF-alpha (rhTNF-α) and explored the effects of MSCs on inflammation and Na+-glucose cotransporter 2 (SGLT2) expression in HK2. RESULTS: We found that MSCs decreased the blood glucose level and daily insulin requirement of DN rhesus macaques. Furthermore, MSCs had a dominant function in improving renal function and decreasing SGLT2 expression on renal tubular epithelial cells. Also, renal pathological changes were ameliorated after MSC treatment. Moreover, MSCs powerfully reduced inflammation, especially decreased the level of pro-inflammatory cytokine interleukin-16 (IL-16), in the kidney and blood circulatory system. CONCLUSIONS: Our study is an important step to explore the mechanism of MSCs in ameliorating the early stage of DN, potentially through influencing SGLT2 expression and resulting in improved glycemic control and anti-inflammation. We hope these findings would provide insights for the clinical application of MSCs in DN.


Assuntos
Nefropatias Diabéticas/terapia , Transplante de Células-Tronco Mesenquimais , Animais , Glicemia/análise , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Hemoglobinas Glicadas/metabolismo , Humanos , Rim/patologia , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/metabolismo , Macaca mulatta , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Índice de Gravidade de Doença , Transportador 2 de Glucose-Sódio/genética , Transportador 2 de Glucose-Sódio/metabolismo , Cordão Umbilical/citologia
2.
Sci Rep ; 9(1): 18729, 2019 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31822751

RESUMO

Among hematological cancers, Acute Lymphoblastic Leukemia (ALL) and Chronic Lymphocytic Leukemia (CLL) are the most common leukemia in children and elderly people respectively. Some patients do not respond to chemotherapy treatments and it is necessary to complement it with immunotherapy-based treatments such as chimeric antigen receptor (CAR) therapy, which is one of the newest and more effective treatments against these cancers and B-cell lymphoma. Although complete remission results are promising, CAR T cell therapy presents still some risks for the patients, including cytokine release syndrome (CRS) and neurotoxicity. We proposed a different immune cell source for CAR therapy that might prevent these side effects while efficiently targeting malignant cells. NK cells from different sources are a promising vehicle for CAR therapy, as they do not cause graft versus host disease (GvHD) in allogenic therapies and they are prompt to attack cancer cells without prior sensitization. We studied the efficacy of NK cells from adult peripheral blood (AB) and umbilical cord blood (CB) against different target cells in order to determine the best source for CAR therapy. AB CAR-NK cells are slightly better at killing CD19 presenting target cells and CB NK cells are easier to stimulate and they have more stable number from donor to donor. We conclude that CAR-NK cells from both sources have their advantages to be an alternative and safer candidate for CAR therapy.


Assuntos
Imunoterapia Adotiva/métodos , Células Matadoras Naturais/transplante , Leucemia/terapia , Idoso , Idoso de 80 Anos ou mais , Antígenos CD19/imunologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Feminino , Sangue Fetal/imunologia , Doença Enxerto-Hospedeiro/etiologia , Humanos , Células Matadoras Naturais/imunologia , Leucemia/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Indução de Remissão
3.
Hematology Am Soc Hematol Educ Program ; 2019(1): 522-531, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31808851

RESUMO

Nowadays a donor can be found for virtually all patients in need of an allogeneic stem cell transplantation, and the decision whether to use a matched or mismatched unrelated donor, an unrelated donor for umbilical cord blood transplantation (UCBT), or a haploidentical donor depends not only on the availability of the donor but also on patient-, disease-, and center-related factors. This paper summarizes the recent criteria in the selection of cord blood unit, including the cell dose requirement and the HLA typing for the optimal donor choice. The main strategies to optimize the results of UCBT, the conditioning regimens, and the use of antithymocyte globulin and the other platforms of graft-versus-host disease prophylaxis are discussed. The paper describes the results of UCBT in children and adults with malignant and nonmalignant diseases and the comparative analysis with other donor type and stem cell sources. Emerging strategies, focusing on the different platforms of ex vivo expansion and the new applications using cord blood stem cell, are also examined.


Assuntos
Anemia Aplástica , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Seleção do Doador , Teste de Histocompatibilidade , Leucemia Mieloide Aguda , Condicionamento Pré-Transplante , Adolescente , Adulto , Anemia Aplástica/sangue , Anemia Aplástica/diagnóstico , Anemia Aplástica/genética , Anemia Aplástica/terapia , Feminino , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino
4.
Blood Adv ; 3(23): 4117-4130, 2019 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31821460

RESUMO

Natural killer (NK) cells are highly heterogeneous, with vast phenotypic and functional diversity at the single-cell level. They are involved in the innate immune response against malignant and virus-infected cells. To understand the effect of NK diversity during immune recovery on the antitumor response after cord blood transplantation (CBT), we used high-dimensional mass cytometry and the metrics of NK cell diversity to study the NK cell repertoire in serial samples from 43 CBT recipients. A higher-diversity index based on single-cell combinatorial phenotypes was significantly associated with a lower risk for relapse after CBT (P = .005). Cytomegalovirus reactivation was a major factor in the development of a more diverse NK repertoire after CBT. Notably, we identified a group of patients whose CB-derived NK cells after transplantation possessed an immature phenotype (CB-NKim), characterized by poor effector function and a low diversity index. Frequencies of CB-NKim of 11.8% or higher during the early post-CBT recovery phase were highly predictive for relapse (area under the curve [AUC], 0.979), a finding that was validated in a second independent cohort of patients (n = 25; AUC, 0.977). Moreover, we showed that the maturation, diversity, and acquisition of effector function by CB-NKim early after CBT were driven by interleukin 15. Our data indicate that the diversity of the NK cell repertoire after CBT contributes importantly to the risk for subsequent relapse. We suggest that the use of diversity metrics and high-dimensional mass cytometry may be useful tools in predicting clinical outcomes and informing the design of therapeutic strategies to prevent relapse after CBT.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Células Matadoras Naturais/imunologia , Humanos , Recidiva
5.
Sci Rep ; 9(1): 19105, 2019 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-31836828

RESUMO

Humanized mice can be used to better understand how the human immune system responds to central nervous system (CNS) injury and inflammation. The optimal parameters for using humanized mice in preclinical CNS injury models need to be established for appropriate use and interpretation. Here, we show that the developmental age of the human immune system significantly affects anatomical and functional outcome measures in a preclinical model of traumatic spinal cord injury (SCI). Specifically, it takes approximately 3-4 months for a stable and functionally competent human immune system to develop in neonatal immune compromised mice after they are engrafted with human umbilical cord blood stem cells. Humanized mice receiving a SCI before or after stable engraftment exhibit significantly different neuroinflammatory profiles. Importantly, the development of a mature human immune system was associated with worse lesion pathology and neurological recovery after SCI. In these mice, human T cells infiltrate the spinal cord lesion and directly contact human macrophages. Together, data in this report establish an optimal experimental framework for using humanized mice to help translate promising preclinical therapies for CNS injury.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/terapia , Animais , Modelos Animais de Doenças , Feminino , Sangue Fetal/citologia , Humanos , Sistema Imunitário , Inflamação , Lipopolissacarídeos , Linfócitos/citologia , Macrófagos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Medula Espinal/patologia , Baço/citologia , Linfócitos T Citotóxicos/citologia
6.
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 , Compostos de Piridínio
7.
F1000Res ; 82019.
Artigo em Inglês | MEDLINE | ID: mdl-31723413

RESUMO

Cord blood (CB) has been used as a viable source of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) in over 35,000 clinical hematopoietic cell transplantation (HCT) efforts to treat the same variety of malignant and non-malignant disorders treated by bone marrow (BM) and mobilized peripheral blood (mPB) using HLA-matched or partially HLA-disparate related or unrelated donor cells for adult and children recipients. This review documents the beginning of this clinical effort that started in the 1980's, the pros and cons of CB HCT compared to BM and mPB HCT, and recent experimental and clinical efforts to enhance the efficacy of CB HCT. These efforts include means for increasing HSC numbers in single CB collections, expanding functional HSCs ex vivo, and improving CB HSC homing and engraftment, all with the goal of clinical translation. Concluding remarks highlight the need for phase I/II clinical trials to test the experimental procedures that are described, either alone or in combination.


Assuntos
Sangue Fetal/citologia , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Humanos
8.
Transplant Proc ; 51(10): 3431-3436, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31733793

RESUMO

This study reports a single-arm trial in the interim phase in 4 patients with median age of 40.5 years who have undergone combined HLA-matched sibling donor (MSD) stem cell graft and an unrelated cord blood (UCB) unit for the treatment of severe aplastic anemia (SAA). The median time was 10 days for neutrophil engraftment (9-18 days) and 17 days for platelets (12-24 days). Median follow-up of 22 months (ranging from 16 to 29 months) showed survival of the 4 patients with complete hematological response. Acute graft-vs-host disease (GVHD) (grade II) occurred only in 1 patient, yet chronic GVHD was free. One patient showed a pattern of transient MSD graft followed by dominant UCB chimerism, and another 1 achieved mixed chimerism in the first 6 months after allogeneic hematopoietic stem cell transplantation (allo-HSCT) then evolved to a stable MSD graft. The other 2 patients sustained a full MSD graft during the post-HSCT period. Nevertheless, none of the patients developed primary and secondary graft failure up to the final follow-up. Although this is a small cohort, the dual transplantation combining HLA-matched sibling allogeneic hematopoietic stem cell transplantation with unrelated cord blood unit may deserve further exploration for treatment of SAA patients aged 35 to 50 years old.


Assuntos
Anemia Aplástica/terapia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Adulto , Quimerismo , Terapia Combinada , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Irmãos , Doadores de Tecidos , Adulto Jovem
9.
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
10.
Regen Med ; 14(11): 1001-1012, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31726959

RESUMO

Aim: We investigated the therapeutic effects and optimal dose of human umbilical cord blood (UCB)-derived mesenchymal stem cell (MSC) injection in a chronic full-thickness rotator cuff tendon tear. Methods: Rabbits (n = 30) were allocated into three groups (normal saline, G1-Sal; 1 × 106 cells UCB-MSC, G2-Low; 2 × 106 cells UCB-MSC, G3-High). Injections were done into the chronic full-thickness rotator cuff tendon tear 6 weeks after a full-thickness tendon tear of the subscapularis was created. Gross & histologic evaluation and motion analysis was done at pre and 4 weeks post-injection. Results: There were no significant differences in tear size and motion analysis parameters 4 weeks after injection between G2-Low and G3-High. Conclusion: The benefits of UCB-MSCs are not dose-dependent in a rabbit model.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Regeneração , Lesões do Manguito Rotador/terapia , Manguito Rotador/patologia , Animais , Bromodesoxiuridina/metabolismo , Doença Crônica , Modelos Animais de Doenças , Sangue Fetal/citologia , Humanos , Injeções , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Coelhos , Lesões do Manguito Rotador/patologia
11.
Ann Hematol ; 98(12): 2815-2823, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31713653

RESUMO

Allogeneic hematopoietic stem cell transplantation (allo-SCT) has been considered as a potentially curative treatment option for refractory or relapsed diffuse large B cell lymphoma (DLBCL) patients. However, there is little information available, especially for Japanese patients and in cord blood transplantation (CBT). We aimed to determine treatment outcomes of allo-SCT for DLBCL in the Kyoto Stem Cell Transplantation Group, a multi-institutional joint research group. Sixty-eight DLBCL patients who underwent their first allo-SCT between 2003 and 2016 were included. The median time from diagnosis to transplantation was 13.5 months. Thirty-one patients were in CR/PR at transplantation. Twenty-seven patients underwent CBT. The median follow-up for survivors was 44.2 months. Four-year overall survival (OS) and relapse-free survival (RFS) rates were 23% (95% CI, 13-35%) and 20% (95% CI, 11-31%), respectively. Cumulative incidences of non-relapse mortality and relapse were 23% and 57%, respectively. Patients in CR/PR at allo-SCT had better OS (4-year, 46% vs 4%, P < 0.001) and RFS (4-year, 36% vs 7%, P = 0.005). The source of the stem cell did not significantly affect OS (4-year, bone marrow vs cord blood vs peripheral blood, 28.6% vs 27.2% vs 6.5%, P = 0.193). In multivariate analysis, non-remission status at SCT associated with inferior OS and RFS. Duration from diagnosis to transplantation of less than 1 year associated with inferior RFS. Allo-SCT, including CBT, may be a promising therapeutic modality for DLBCL patients who have good disease control at transplantation.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Linfoma Difuso de Grandes Células B , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Japão/epidemiologia , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
12.
Expert Rev Hematol ; 12(12): 1089-1094, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31607188

RESUMO

Background: Umbilical cord blood transplantation is an effective method of curing multiple diseases when there is no donor available for allogeneic hematopoietic stem cell transplantation (AHSCT). It has been recently suggested that polymorphisms in genes affecting antigen presentation could potentially affect cord blood transplantation (CBT) outcomes.Areas covered: In this review, we present the results of the latest studies investigating the link between CTLA4 gene variability and umbilical cord blood transplantation outcomes.Expert opinion: The search for genetic variants that influence the immune response, both innate and adaptive immunity, may lead to more optimal therapies. Promising candidate genes are those that regulate the expression of proteins associated with T-cell activation. Many genetic variants could be therapeutically important, including those related to innate and adaptive immunity, cytokines, chemokines, drug-metabolizing enzymes, drug transporters, and inflammatory enzymes. The development of an algorithm that includes the determination of selected genetic variants could be helpful for an appropriate donor-recipient CBT matching.


Assuntos
Apresentação de Antígeno/genética , Antígeno CTLA-4 , Genótipo , Imunidade Inata/genética , Ativação Linfocitária/genética , Linfócitos T/imunologia , Aloenxertos , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Citocinas/genética , Citocinas/imunologia , Humanos , Linfócitos T/patologia , Resultado do Tratamento
14.
Blood Adv ; 3(20): 2934-2948, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31648315

RESUMO

Broader clinical application of umbilical cord blood (UCB), as a source of hematopoietic stem/progenitor cells (HSPCs), is limited by low CD34+ and T-cell numbers, contributing to slow lymphohematopoietic recovery, infection, and relapse. Studies have evaluated the safety, feasibility, and expedited neutrophil recovery associated with the transplantation of CD34+ HSPCs from ex vivo expansion cultures using the aryl hydrocarbon receptor antagonist StemRegenin-1 (SR1). In a phase 1/2 study of 17 patients who received combined SR1-expanded and unexpanded UCB units, a considerable advantage for enhancing T-cell chimerism was not observed. We previously showed that progenitor T (proT) cells generated in vitro from HSPCs accelerated T-cell reconstitution and restored immunity after hematopoietic stem cell transplantation (HSCT). To expedite immune recovery, we hypothesized that SR1-expanded HSPCs together with proT cells could overcome the known T-cell immune deficiency that occurs post-HSCT. Here, we show that SR1-expanded UCB can induce >250-fold expansion of CD34+ HSPCs, which can generate large numbers of proT cells upon in vitro differentiation. When compared with nonexpanded naive proT cells, SR1 proT cells also showed effective thymus-seeding and peripheral T-cell functional capabilities in vivo despite having an altered phenotype. In a competitive transfer approach, both naive and SR1 proT cells showed comparable thymus-engrafting capacities. Single-cell RNA sequencing of peripheral CD3+ T cells from mice injected with either naive or SR1 proT cells revealed functional subsets of T cells with polyclonal T-cell receptor repertoires. Our findings support the use of SR1-expanded UCB grafts combined with proT-cell generation for decreasing T-cell immunodeficiency post-HSCT.


Assuntos
Antígenos CD34/metabolismo , Diferenciação Celular , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Células Precursoras de Linfócitos T/citologia , Células Precursoras de Linfócitos T/metabolismo , Purinas/metabolismo , Animais , Biomarcadores , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Movimento Celular , Células Cultivadas , Evolução Clonal , Técnicas de Cocultura , Sangue Fetal/citologia , Perfilação da Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunofenotipagem , Camundongos , Camundongos Transgênicos
15.
Nat Med ; 25(10): 1566-1575, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31591594

RESUMO

The ability to expand hematopoietic stem and progenitor cells (HSPCs) ex vivo is critical to fully realize the potential of HSPC-based therapies. In particular, the application of clinically effective therapies, such as cord blood transplantation, has been impeded because of limited HSPC availability. Here, using 3D culture of human HSPCs in a degradable zwitterionic hydrogel, we achieved substantial expansion of phenotypically primitive CD34+ cord blood and bone-marrow-derived HSPCs. This culture system led to a 73-fold increase in long-term hematopoietic stem cell (LT-HSC) frequency, as demonstrated by limiting dilution assays, and the expanded HSPCs were capable of hematopoietic reconstitution for at least 24 weeks in immunocompromised mice. Both the zwitterionic characteristics of the hydrogel and the 3D format were important for HSPC self-renewal. Mechanistically, the impact of 3D zwitterionic hydrogel culture on mitigating HSPC differentiation and promoting self-renewal might result from an inhibition of excessive reactive oxygen species (ROS) production via suppression of O2-related metabolism. HSPC expansion using zwitterionic hydrogels has the potential to facilitate the clinical application of hematopoietic-stem-cell therapies.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Terapia Baseada em Transplante de Células e Tecidos , Células-Tronco Hematopoéticas/citologia , Hidrogéis/farmacologia , Animais , Antígenos CD34/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Técnicas de Cultura de Células , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Sangue Fetal/citologia , Sangue Fetal/metabolismo , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos , Espécies Reativas de Oxigênio/metabolismo
17.
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
18.
Cytotherapy ; 21(11): 1112-1121, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31587876

RESUMO

Clinical use of umbilical cord blood (UCB) for novel indications in regenerative therapy continues to rise, however, whether new indications are proven is less clear. An updated systematic search of the literature, focusing only on controlled clinical studies, is needed to properly assess potential efficacy. After updating our systematic search to April 1, 2018 (PROSPERO protocol CRD42016040157), a total of 16 studies were identified that addressed the treatment of cerebral palsy (four studies), type 1 diabetes (three studies), and nine other novel potential indications where only a single controlled study was identified. In the four controlled studies of patients with cerebral palsy, three used allogeneic cells and reported greater improvement in motor-related scores at 1, 3 and 6 months compared with controls. The results were mixed for other scores at other time points, including additional measures of mental and motor function. One study of autologous UCB treatment reported an improvement in motor function scores at 12 months compared with controls. In the three controlled studies of type 1 diabetes, two studies used autologous cells whereas one used allogeneic cord blood cells to "educate" autologous lymphocytes. Taken together, there was no clear difference in HbA1c levels or daily insulin requirements between treated patients and controls. For the nine published reports with a single controlled study, eight used allogeneic UCB cells and seven infused mesenchymal stromal cells derived from UCB. All but one study reported benefit. Many other published reports that lack a control group were not included in our analysis. More controlled studies are needed that use similar approaches regarding cell source and outcome measures at similar time points. Pooled estimates of results from multiple studies will be essential as published studies remain modest in size. Patients should continue to be enrolled in clinical trials because there are no novel potential indications remain unproven.


Assuntos
Ensaios Clínicos Controlados como Assunto/estatística & dados numéricos , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Sangue Fetal/fisiologia , Medicina Regenerativa , Paralisia Cerebral/terapia , Ensaios Clínicos Controlados como Assunto/normas , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/normas , Transplante de Células-Tronco de Sangue do Cordão Umbilical/estatística & dados numéricos , Diabetes Mellitus Tipo 1/terapia , Sangue Fetal/citologia , Humanos , Recém-Nascido , Células-Tronco Mesenquimais , Medicina Regenerativa/métodos , Medicina Regenerativa/estatística & dados numéricos , Medicina Regenerativa/tendências
19.
Int J Mol Sci ; 20(19)2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31575081

RESUMO

Hematopoietic progenitor cell (HPC) transplantation is a treatment option for malignant and nonmalignant diseases. Umbilical cord blood (UCB) is an important HPC source, mainly for pediatric patients. It has been demonstrated that human leukocyte antigen (HLA) matching and cell dose are the most important features impacting clinical outcomes. However, UCB matching is performed using low resolution HLA typing and it has been demonstrated that the unnoticed mismatches negatively impact the transplant. Since we found differences in CD34+ viability after thawing of UCB units matched for two different patients (p = 0.05), we presumed a possible association between CD34+ cell viability and HLA. We performed a multivariate linear model (n = 67), comprising pre-cryopreservation variables and high resolution HLA genotypes separately. We found that pre-cryopreservation red blood cells (RBC), granulocytes, and viable CD34+ cell count significantly impacted CD34+ viability after thawing, along with HLA-B or -C (R2 = 0.95, p = 0.01; R2 = 0.56, p = 0.007, respectively). Although HLA-B*40:02 may have a negative impact on CD34+ cell viability, RBC depletion significantly improves it.


Assuntos
Comunicação Celular , Eritrócitos/metabolismo , Sangue Fetal/citologia , Antígenos HLA/genética , Células-Tronco Hematopoéticas/metabolismo , Alelos , Antígenos CD34/metabolismo , Comunicação Celular/genética , Sobrevivência Celular/genética , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Criopreservação , Células-Tronco Hematopoéticas/citologia , Humanos
20.
Stem Cells Dev ; 28(22): 1486-1497, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31552804

RESUMO

Hematopoietic stem cell (HSC) transplantation therapy is one of the most effective treatments for life-threatening hematopoietic diseases. Bone marrow (BM) and mobilized peripheral blood are the major sources of HSCs, but these resources are limited by a paucity of human leukocyte antigen (HLA)-matched donors. Umbilical cord blood (UCB) is the most promising alternative to obtain HSCs for transplantation therapy. However, UCB transplantation therapy is limited by low numbers of HSCs per unit of UCB. In vitro HSC expansion is believed to be the most effective and applicable strategy to address this issue. Here we report that a moderate concentration of GSK3 inhibitor promotes HSC expansion by inducing moderate levels of ß-catenin activity in HSCs. However, such a concentration of GSK3 inhibitor also stimulates myeloid cells to produce inflammatory cytokines, which attenuate HSC expansion by inducing p38 activation. Thus, when unpurified HSCs were used in culture, inhibition of p38-induced inflammatory cytokine signaling was required to ensure HSC expansion induced by the low concentration of GSK3 inhibitor. Our study suggests that the combination of a moderate concentration of p38 inhibitor plus a GSK3 inhibitor synergistically promotes the expansion of both murine BM HSCs and human UCB HSCs.


Assuntos
Sangue Fetal/transplante , Quinase 3 da Glicogênio Sintase/genética , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Animais , Células da Medula Óssea/citologia , Transplante de Medula Óssea , Diferenciação Celular/genética , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Sangue Fetal/citologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Antígenos HLA/genética , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/imunologia , Células-Tronco Hematopoéticas/citologia , Heparina/farmacologia , Humanos , Camundongos , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
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