Transición a la medicina del adulto en sobrevivientes de un trasplante alogénico de células progenitoras hematopoyéticas / Transition to adult medicine in survivors of allogeneic hematopoietic stem cell transplantation

Los sobrevivientes de un trasplante alogénico de células progenitoras hematopoyéticas (TACPH) pediátrico presentan alto riesgo de padecer problemas de salud. Debido a esta vulnerabilidad, la continuidad del cuidado impacta en su pronóstico y la transición a la medicina del adulto (TMA) es un proceso clave. Objetivo: Evaluar el proceso actual de TMA de los receptores de TACPH en nuestro hospital. Métodos: Diseño: observacional retrospectivo y prospectivo. Población: todos los pacientes (p) que realizaron su TMA desde enero/2022 a marzo/2023. Instrumentos: entrevista personal; material escrito; resumen de historia clínica; escalas TRAQ 5.0 (transición), PedsQL 4.0 (CVRS) y Lansky (funcionalidad); elección de estrategias de seguimiento según complejidad y requerimientos; contacto con profesionales de adultos; entrevista telefónica luego de 6 meses posTMA; red conformada. Resultados: 36p completaron la TAM (33 presencial, 3 virtual). Edad m19 años (m6 años de seguimiento), 70% del interior del país, 58% TACPH por enfermedad maligna, 64% TACPH familiar. A la TMA: antecedente EICHc 50%, segunda enfermedad maligna 2%, compromiso órganos 75% (m2/p, r0-8, mayormente endocrinológicas, oculares y neurológicas), 94% Lansky ≥80 (r50-100), PedsQL m82 (27% ≤75), TRAQ m3.4 (r1.7- 4.8). Derivación: todos los p cubrían sus necesidades (30% en centros de alta complejidad o expertos en THA) pero 3p debieron readecuar las estrategias, 5p presentaban complicaciones en actividad o necesidad de pronta resolución. Contacto posterior: 30/33p continuaban seguimiento, 3p pudieron retomarlo, 9p nuevas complicaciones/tratamientos. Red: 20 profesionales/instituciones. Conclusiones: Se refuerza la necesidad y utilidad de un proceso de TMA tanto formal como personalizado según necesidades individuales de los pacientes con TACPH (AU)

Pediatric allogeneic hematopoietic stem cell transplant (HSCT) survivors are at high risk for health problems. Because of this vulnerability, continuity of care impacts their prognosis and transition to adult medicine (TAM) is a key process. Objective: To evaluate the current process of TAM of HSCT recipients in our hospital. Methods: A retrospective and prospective observational study was conducted. The population included all patients (p) who underwent TAM from January 2022 to March 2023. Instruments used included personal interviews, written materials, medical history summaries, the TRAQ 5.0 (transition), PedsQL 4.0 (HRQoL), and Lansky (functionality) scales. Follow-up strategies were chosen according to complexity and requirements, with contact established with adult professionals and a telephone interview conducted six months post-TAM in an established network network. Results: 36p completed TAM (33 face-to-face, 3 online). Mean age was 19 years (with a mean of 6 years of follow-up); 70% were from the provinces of the country, 58% underwent HSCT due to malignant disease, 64% had familial HSCT. At TAM: 50% had a history of GVHD, 2% had a second malignant disease, and 75% had organ involvement (mean of 2 per patient, ranging from 0 to 8, mostly endocrinological, ocular, and neurological), 94% had Lansky ≥80 (range, 50-100), mean PedsQL was 82 (27% ≤75), mean TRAQ was 3.4 (range, 1.7-4.8). Referral needs were met for all patients (30% in tertiary-level centers or with experts in allogeneic HSCT), although 3 patients had to readjust strategies, and 5 had complications requiring prompt resolution. In subsequent contact, 30 out of 33 patients continued follow-up, 3 resumed it, and 9 experienced new complications or treatments. The network included 20 healthcare providers/institutions. Conclusions: This study reinforces the need for and usefulness of a formal and personalized TAM process according to the individual needs of patients with HSCT (AU)

Therapeutic Choices in Patients with Ph-Positive Chronic Myelogenous Leukemia In Mexico in the Era of Tyrosine Kinase Inhibitors: Stem Cell Transplantation or Tyrosine Kinase Inhibitors? Fifteen Years Later

ABSTRACT Background: Chronic myelogenous leukemia is a neoplastic proliferation of the granulocytic series. In Mexico, chronic myelogenous leukemia accounts for approximately 10% of all leukemias. Tyrosine-kinase inhibitors are considered front-line therapy in high-income countries, whereas allogeneic hematopoietic stem cell transplantation is a recognized therapeutic approach, mainly in low- and middle-income countries. Objective: To analyze the overall survival of persons with chronic myelogenous leukemia who have received tyrosine-kinase inhibitors or allogeneic hematopoietic stem cell transplantation in a medical center, since 1994, and briefly discuss the current indications of these treatments in the tyrosine-kinase inhibitors era. Methods: We retrospectively analyzed all patients with a diagnosis of chronic myelogenous leukemia treated in a medical center between 1994 and 2023; subsets of individuals who received an allogeneic hematopoietic stem cell transplantation or tyrosine-kinase inhibitors therapy as first-line treatment were analyzed. Results: 60 persons with chronic myelogenous leukemia were treated with allogeneic hematopoietic stem cell transplantation or tyrosine-kinase inhibitors: 35 received an allogeneic hematopoietic stem cell transplantation, whereas 25 were given tyrosine-kinase inhibitors. All patients who underwent an allogeneic hematopoietic stem cell transplantation engrafted successfully, and the procedure was completed on an outpatient basis in most cases (29/35). The median survival in allogeneic hematopoietic stem cell transplantation was 78.3 months (CI 95%: 0-205.6) and in persons given tyrosine-kinase inhibitors the median was not reached. Conclusion: Tyrosine-kinase inhibitors were significantly superior to allogeneic hematopoietic stem cell transplantation in prolonging the overall survival of persons with chronic myelogenous leukemia in our single institution experience. (Rev Invest Clin. 2024;76(2):91-6)

Número de células CD34+ circulantes como predictor de recolección exitosa de progenitores hematopoyéticos por aféresis en trasplante autólogo / Number of circulating CD34+ cells as a predictor of successful collection of hematopoietic progenitors by apheresis in autologous transplantation

RESUMEN Introducción. El trasplante autólogo de células progenitoras hematopoyéticas es una terapia eficaz en neoplasias malignas hematológicas. El número de células que CD34+ en sangre periférica es el mejor predictor del rendimiento de recolección de células progenitoras hematopoyéticas. Objetivo. Determinar el número de células CD34+ en sangre periférica asociado al éxito de recolección de progenitores hematopoyéticos por aféresis en trasplante autólogo. Métodos. Se evaluó retrospectivamente los datos de 236 procedimientos de aféresis de células progenitoras hematopoyéticas para el trasplante autólogo en el Hospital Edgardo Rebagliati Martins (Lima, Perú) de julio del 2020 a julio del 2023. Se utilizó la curva ROC (características operativas del receptor) para determinar el número de células CD34+ en sangre periférica necesario para lograr una recolección por aféresis ≥ 2 x 106 células CD34+/kg. Resultados. El 61% fueron hombres, con mediana de edad de 58 años, el valor de corte fue de 18,38 células CD34+/μL (sensibilidad de 94,1% y especificidad de 96,9%). Conclusión. El número de células CD34+ sangre periférica para una recolección exitosa de células progenitoras hematopoyéticas para el trasplante autólogo fue de 18,38 células CD34+/μL.

ABSTRACT Introduction. Autologous hematopoietic progenitor cell transplantation is an effective therapy in hematological malignancies, the number of CD34+ cells in peripheral blood is the best predictor of hematopoietic progenitor cell harvesting performance. Objective. To determine the number of CD34+ cells in peripheral blood associated with the successful collection of hematopoietic progenitors by apheresis in autologous transplantation. Methods. The data of 236 hematopoietic progenitor cell apheresis procedures for autologous transplantation at the Edgardo Rebagliati Martins Hospital (Lima, Peru) were retrospectively evaluated from July 2020 to July 2023. The ROC (receiver operating characteristics) curve was used to determine the number of CD34+ cells in peripheral blood necessary to achieve an collection by apheresis ≥ 2 x 106 CD34+ cells/kg. Results. 61% were men, with a median age of 58 years, the cut-off value was 18.38 CD34+ cells/μL (sensitivity of 94.1% and specificity of 96.9%). Conclusion. The number of peripheral blood CD34+cells for successful collection of hematopoietic progenitor cells for autologous transplantation was 18.38 CD34+ cells/μL.

Trasplante de médula ósea haploidéntico en un paciente pediátrico con síndrome de Wiskott-Aldrich. A propósito de un caso / Haploidentical bone marrow transplantation in a pediatric patient with Wiskott-Aldrich syndrome. A case report

El síndrome de Wiskott-Aldrich es un error innato de la inmunidad de herencia ligada al cromosoma X, producido por variantes en el gen que codifica la proteína del síndrome de Wiskott-Aldrich (WASp). Reportamos el caso clínico de un paciente de 18 meses con diagnóstico de Wiskott-Aldrich que no presentaba donante antígeno leucocitario humano (HLA) idéntico y recibió un trasplante de células progenitoras hematopoyéticas (TCPH) con donante familiar haploidéntico. La profilaxis para enfermedad de injerto contra huésped incluyó ciclofosfamida (PT-Cy). El quimerismo del día +30 fue 100 % del donante y la evaluación postrasplante de la expresión de la proteína WAS fue normal. Actualmente, a 32 meses del trasplante, presenta reconstitución hematológica e inmunológica y quimerismo completo sin evidencia de enfermedad injerto contra huésped. El TCPH haploidéntico con PT-Cy se mostró factible y seguro en este caso de síndrome de WiskottAldrich en el que no se disponía de un donante HLA idéntico.

Wiskott-Aldrich syndrome (WAS) is an X-linked genetic disorder caused by mutations in the gene that encodes the Wiskott-Aldrich syndrome protein (WASp). Here, we report the clinical case of an 18-month-old boy diagnosed with Wiskott-Aldrich syndrome, who did not have an HLA-matched related or unrelated donor and was treated successfully with a hematopoietic stem cell transplant (HSCT) from a haploidentical family donor. Graft-versus-host disease (GvHD) prophylaxis included post-transplant cyclophosphamide (PT-Cy). At day +30, the peripheral blood-nucleated cell chimerism was 100% and the WAS protein had a normal expression. Currently, at month 32 post-transplant, the patient has hematological and immune reconstitution and complete donor chimerism without evidence of GvHD. HSCT with PT-Cy was a feasible and safe option for this patient with WAS, in which an HLA matched donor was not available.

Research advances in hepatic sinusoidal obstruction syndrome / 临床肝胆病杂志

Hepatic sinusoidal obstruction syndrome （HSOS）， also known as hepatic veno-occlusive disease， is hepatic vascular disease of hepatic sinusoidal obstruction and hepatic venular occlusion and fibrosis due to various causes. This article systematically elaborates on the research advances in HSOS from the aspects of understanding and naming， etiology and pathogenesis， clinical manifestation， diagnosis and differential diagnosis， prevention， and treatment. HSOS can occur in patients receiving bone marrow hematopoietic stem cell transplantation， radiotherapy/chemotherapy， and medication containing pyrrolidine alkaloids， and the common clinical manifestations of HSOS include abdominal distension， distending pain in the liver area， ascites， jaundice， and hepatomegaly. The diagnostic criteria for HSOS vary with etiology， and it needs to be differentiated from other diseases such as drug-induced liver diseases and hepatic venous outflow tract obstruction. Defibrotide and low-molecular-weight heparin have a therapeutic effect on HSOS associated with hematopoietic stem cells and pyrrolidine alkaloids， respectively， and there are currently no effective drugs for HSOS caused by oxaliplatin chemotherapy.

Clinical analysis of lung transplantation for lung chronic graft-versus-host disease after hematopoietic stem cell transplantation / 器官移植

<b>Objective</b> To evaluate clinical efficacy of lung transplantation for lung chronic graft-versus-host disease (cGVHD) after hematopoietic stem cell transplantation (HSCT). <b>Methods</b> Clinical data of 12 patients undergoing lung transplantation for lung cGVHD were retrospectively analyzed. Preoperative clinical manifestations and involved organs of patients were analyzed. The lung function before and after lung transplantation was compared, and the survival of patients after lung transplantation was analyzed. <b>Results</b> Eleven patients underwent HSCT due to primary hematological malignancies, including 9 cases of leukemia, 1 case of myelodysplastic syndrome, 1 case of lymphoma. And 1 case underwent HSCT for systemic lupus erythematosus. Among 12 cGVHD patients, skin involvement was found in 8 cases, oral cavity involvement in 5 cases, gastrointestinal tract involvement in 4 cases and liver involvement in 3 cases. All 12 patients developed severe respiratory failure caused by cGVHD before lung transplantation, including 9 cases of typeⅡ respiratory failure and 3 cases of type Ⅰ respiratory failure. Two patients underwent right lung transplantation, 2 cases of left lung transplantation and 8 cases of bilateral lung transplantation. The interval from HSCT to lung transplantation was 75 (19-187) months. Upon the date of submission, postoperative follow-up time was 18 (7-74) months. Ten patients survived, 1 died from severe hepatitis at postoperative 22 months, and 1 died from gastrointestinal bleeding at postoperative 6 months. No recurrence of primary diseases was reported in surviving patients. <b>Conclusions</b> Lung transplantation is an efficacious treatment for lung cGVHD after HSCT, which may prolong the survival time and improve the quality of life of the recipients.

Diagnosis and treatment progress of liver injury after allogeneic hematopoietic stem cell transplantation / 白血病·淋巴瘤

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative method for various hematological diseases. With the optimization of transplantation technology, the clinical application of allo-HSCT is more and more mature. Post-transplant liver injury is one of the common postoperative complications, which seriously affects the quality of life and long-term survival of patients. The causes of liver injury after allo-HSCT can be divided into non-infectious and infectious factors, which show similar clinical manifestations and different treatment principles. Timely diagnosis of post-transplant liver injury and the identification of the disease cause will be beneficial for early prevention or targeted treatment, thereby improving patients' prognosis. This review focuses on the etiology, clinical features, and treatment options of liver injury after allo-HSCT, aiming to deepen the understanding of hematologists on liver injury after allo-HSCT.

Effects of anti-HLA donor-specific antibodies and desensitization on engraftment of haploidentical hematopoietic stem cell transplantation / 陆军军医大学学报

Objective To investigate the effects of anti-HLA donor-specific antibodies(DSA)and desensitization for DSA+patients on engraftment of haploidentical hematopoietic stem cell transplantation(haplo-HSCT).Methods The patients who underwent haplo-HSCT and examinations for HLA antibodies and DSA in our department from March 2017 to July 2023 were recruited in this study.The effects of desensitization measure on engraftment in the DSA+patients after haplo-HSCT were analyzed.Results Among the 70 patients who underwent haplo-HSCT and test for HLA antibodies,15(21.4％)patients were DSA positive,including 7(46.7％)cases of strong positive,3(20.0％)cases of moderate positive,and 5(33.3％)cases of weak positive.The median duration for neutrophil implantation was significantly extended in the DSA+patients than the negative patients(P=0.027).For the 6 patients developed graft failure(GF),4 were DSA+which was statistically higher than the DSA-patients(P=0.025).Multivariate regression analysis showed that DSA was an independent factor affecting GF(HR=9.273,95％CI:1.505～57.124,P=0.016).Among the 10 patients(7 strong positive and 3 moderate positive DSA)received desensitization therapy,4 patients received combination desensitization,with a 100％rate of successful transplantation,and 6 received single desensitization,with 4(66.7％)experiencing GF,so the GF rate was obviously lower in the combination than the single desensitization(P=0.008).Conclusion In haplo-HSCT patients,DSA is an important factor leading to implantation delay and GF.While,single desensitization treatment has limited efficacy.In combined DSA desensitization therapy,the decrease of antibody titer should be dynamically monitored to ensure the successful implantation of stem cells and reduce GF rate.

Association of intestinal and oral microbiota with acute graft versus host disease of the gastrointestinal tract in patients after allogeneic hematopoietic stem cell transplantation / 陆军军医大学学报

Objective To preliminarily investigate the association between changes in intestinal microbiota and oral microbiota of allogeneic hematopoietic stem cell transplantation(allo-HSCT)patients and early gastrointestinal acute graft versus host disease(aGVHD),and try to explore potentially effective biomarkers and provide theoretical basis for early prediction and intervention of gastrointestinal aGVHD.Methods Ten acute leukemia patients who developed gastrointestinal aGVHD within 1 month after receiving allo-HSCT in Department of Hematology of Sichuan Provincial People's Hospital from September 2021 to June 2023 were enrolled,and their fecal samples and saliva samples before and after the aGVHD were collected.16S rRNA sequencing analysis was applied for the differential changes in intestinal and oral microbiota before and after the development of early gastrointestinal aGVHD.Results ① A decrease in Bacteroides spp.and an increase in Enterococcus spp.and Enterobacteriaceae spp.in the intestinal microbiota were positively correlated with the occurrence of early upper gastrointestinal aGVHD(P＜0.05),whereas no significant difference was observed in the overall microbial diversity of the oral microbiota(P＞0.05).② LEfSe analysis of the intestinal microbiota before and after gastrointestinal aGVHD revealed an increase in Klebsiella spp.and Enterococcus spp.and a decrease in Escherichia coli;In the oral microbiota,LEfSe analysis revealed 10 microbial markers with significant difference,of which Gamma proteobacteria was the most significant.③ The difference in β-diversity of the intestinal microbiota was significant(P=0.03),whereas there was no significant difference in the α-and β-diversity of the oral microbiota.Conclusion Significant differences are found in intestinal microbiota before and after the occurrence of early gastrointestinal aGVHD in patients after Allo-HSCT,and the occurrence may have a correlation with the chang in oral microbiota.

Advances in treatment of acute leukemia and long-term ovarian function in children and adolescents / 国际儿科学杂志

Acute leukemia（AL）is a common hematological malignancy in children and adolescents. Chemotherapy is currently the primary treatment for AL.Alternative therapies，such as hematopoietic stem cell transplantation（HSCT），targeted therapy，and immunotherapy also offer greater hope for the survival of refractory/relapsed patients. Chemotherapeutic drugs，radiotherapy，targeted drugs and immunotherapeutic drugs are well-applied clinically，meanwhile posing threats to non-target systems. The adverse effects on the reproductive system may lead to the dilemma of infertility，thus reducing the long-term quality of life. As the survival rate of AL patients keeps increasing continuously，the influence of different treatments on the gonad function needs to be clarified. With the help of targeted fertility prevention，the patient′s quality of life can be enhanced in parallel with life span. This article aims to review the impact of AL treatment on ovarian function in female children and adolescents and provide ideas for the long-term fertility protection of leukemia patients.

Research progress on the return to work of survivors of hematopoietic stem cell transplantation / 中国实用护理杂志

This paper provided a comprehensive review of the concept, current situation and influencing factors of survivors returning to work after hematopoietic stem cell transplantation, both in domestic and international contexts. The research analyzed and elaborates on four aspects of individual factors, disease-related factors, occupational factors, and social support, in order to provide references for constructing an intervention program for the return to work of hematopoietic stem cell transplantation survivors based on the cultural background in China.

Care of a child with human herpesvirus-6B encephalitis after chimeric antigen receptor T-cell therapy / 中国实用护理杂志

Summarizing the nursing experience of a child with HHV-6B encephalitis after umbilical cord blood transplantation and CAR-T therapy. The child was 4 years old and was diagnosed with acute T lymphocytic leukemia on May 28, 2021. Nursing points: meticulously observe symptoms for early diagnosis and treatment; develop a specialized management plan, implement individualized care; enhance medication management to improve the quality of care; establish a shared decision-making communication model to prevent hospital-acquired infections; provide patient-centered care for lumbar puncture; assess the needs of the child and family, alleviate negative emotions; improve pre-discharge preparation, emphasize continuity of care. With proactive treatment and careful nursing, the child′s condition improved, and they were discharged. Follow-up for six months showed the child in a sustained remission state with no adverse sequelae, and normal life resumed.

Effect of CD34+ cell dose on haploidentical hematopoietic stem cell transplantation for treating malignant hematological diseases / 中国组织工程研究

BACKGROUND:Haploidentical hematopoietic stem cell transplantation is associated with a higher rate of graft rejection and therefore often requires a higher CD34+ cell dose,but the findings reported in existing studies regarding the relationship between CD34+ cell dose and study endpoints after allogeneic hematopoietic stem cell transplantation are controversial. OBJECTIVE:To investigate the effect of CD34+ cell dose on clinical outcomes of haploidentical hematopoietic stem cell transplantation for malignant hematological diseases. METHODS:135 patients who underwent haploidentical hematopoietic stem cell transplantation at Hematopoietic Stem Cell Transplantation Center,Department of Hematology,First Affiliated Hospital of Zhengzhou University between January 2019 and December 2021 were included.Combining the results of previous studies and our center's experience,the cohort was divided into two groups using a CD34+ cell count of 5.0×106/kg as the cut-off point.Clinical outcomes related to graft implantation,relapse incidence,non-relapse mortality,overall survival and progression-free survival were evaluated in both groups. RESULTS AND CONCLUSION:(1)CD34+ cell dose correlated with platelet engraftment,with platelets implanted earlier in the high-dose group than in the low-dose group(14 days vs.16 days,P=0.013).(2)There was no significant difference in 3-year overall survival between the two groups(67.5%vs.53.8%,P=0.257);nor was there a significant difference in progression-free survival between the two groups(65.6%vs.44.2%,P=0.106),but stratified analysis based on disease risk index revealed an association with elevated 3-year progression-free survival in the high-dose group among low-risk patients(72.0%vs.49.3%,P=0.036).(3)The cumulative 3-year relapse incidence was smaller in the high-dose group than in the low-dose group(16.0%vs.33.5%,P=0.05).(4)The rate of non-relapse mortality within 100 days was greater in the high-dose group than in the low-dose group,but there was no significant difference(17.3%vs.6.7%,P=0.070);stratified analysis revealed that non-relapse mortality within 100 days was significantly higher in the high-dose group than in the low-dose group(20.0%vs.3.3%,P=0.046).(5)In conclusion,CD34+ cell doses>5.0×106/kg promote early platelet implantation,improve 3-year progression-free survival in low-risk patients at transplantation and reduce the cumulative relapse incidence.However,in high-risk patients,high-dose CD34+ cells result in increased non-relapse mortality within 100 days after transplantation,which is considered to be possibly associated with an increased occurrence of severe acute graft versus host disease in the early post-transplantation period.Therefore,it is considered that graft versus host disease monitoring should be enhanced in patients who transfused high-dose CD34+ cells.

Hyaluronic acid hydrogel-encapsulated bone marrow mesenchymal stem cells promote cardiac function in myocardial infarction rats(Ⅲ) / 中国组织工程研究

BACKGROUND:Our previous experimental results have shown that hyaluronic acid hydrogel can act as a vehicle for bone marrow mesenchymal stem cell delivery to improve the cardiac function of rats with myocardial infarction. OBJECTIVE:To explore the molecular mechanism of bone marrow mesenchymal stem cells and hyaluronic acid hydrogel in promoting damaged heart repair. METHODS:Bone marrow mesenchymal stem cells from male Sprague-Dawley rats were isolated and cultured,and then hyaluronic acid-encapsulated bone marrow mesenchymal stem cells were cultured in vitro in a three-dimensional manner.A model of myocardial infarction was made by ligating the left anterior descending artery of female Sprague-Dawley rats.After 1 week,the model rats were screened by ultrasonic testing and then eligible ones were randomly divided into four groups:PBS group(n=12),hyaluronic acid group(n=12),bone marrow mesenchymal stem cell group(n=15),and hyaluronic acid-encapsulated bone marrow mesenchymal stem cell group(n=15).At 1 week after ligation,the model rats underwent the secondary thoracotomy followed by corresponding injections into the infarcted region and its marginal zone.The expression levels of matrix metalloproteinase-2,vascular endothelial growth factor,thymosin β4 and c-Kit were examined at post-injection day 1,week 1 and week 2 by western blot assay.At post-injection week 2,immunofluorescence staining was used to detect the differentiation of transplanted cells. RESULTS AND CONCLUSION:(1)The expression levels of matrix metalloproteinase-2 and vascular endothelial growth factor protein in the infarct zone in the bone marrow mesenchymal stem cell group were significantly up-regulated at week 1 compared with the other three groups(P<0.05).At week 2,the hyaluronic acid group had a lower expression of matrix metalloproteinase-2 and vascular endothelial growth factor protein than the other three groups(P<0.05).However,the expression of matrix metalloproteinase-2 and vascular endothelial growth factor protein in the hyaluronic acid+bone marrow mesenchymal stem cell group was not significantly different compared with the bone marrow mesenchymal stem cell group.This was primarily attributable to a prolonged paracrine effect via the controlled release of the hyaluronic acid hydrogel.This prolonged paracrine effect offsets the inhibitory effect induced by hyaluronic acid hydrogel at 2 weeks.(2)Compared with the PBS group,thymosin β4 and c-Kit expression levels in the hyaluronic acid group,bone marrow mesenchymal stem cell group and bone marrow mesenchymal stem cell+hyaluronic acid group were significantly increased(P<0.05).(3)No differentiation of transplanted cells into cardiomyocytes or blood vessels was detected 2 weeks after transplantation.(4)It is indicated that transplanted bone marrow mesenchymal stem cells promote myocardial repair through the paracrine effect,and hyaluronic acid hydrogel prolongs the paracrine effect of transplanted bone marrow mesenchymal stem cells.

Combination of 1％ platelet-rich plasma and bone marrow mesenchymal stem cells improves the recovery of peripheral nerve injury / 中国组织工程研究

BACKGROUND:Platelet-rich plasma has been shown to enhance the viability and the pro-angiogenesis capacity of mesenchymal stem cells.Extracellular vesicles are one of the key mediators for mesenchymal stem cells to exert their effects,but currently,it is unclear whether platelet-rich plasma affects the functions of extracellular vesicles. OBJECTIVE:To investigate the effects of platelet-rich plasma on the function of extracellular vesicles from bone marrow mesenchymal stem cells,verify whether platelet-rich plasma can be used as an adjuvant to enhance the healing effects of bone marrow mesenchymal stem cells on repairing the peripheral nerve injury. METHODS:For in vitro study,bone marrow mesenchymal stem cells were cultured under normal conditions and with 1%platelet-rich plasma.The ultracentrifugation was used to extract the extracellular vesicles produced by bone marrow mesenchymal stem cells cultured under normal conditions(EVs-nor)or the condition supplemented with 1%platelet-rich plasma(EVs-prp).Extracellular vesicles were used to incubate with Schwann cells.The EdU assay,western blot assay,qPCR and light microscopy photography were performed to examine the effects of EVs-nor and EVs-prp on Schwann cell reprogramming,which was characterized by cell proliferation,c-Jun expression,reprogramming-associated gene expression and cell morphology.For in vivo study,the model of sciatic nerve injury in rats was established.Bone marrow mesenchymal stem cells were grafted with or without 1%platelet-rich plasma into the injured rat sciatic nerve using a chitin nerve conduit.Eight weeks after the surgery,the recovery was assessed by histological and functional indexes,including regenerated nerve fiber density,gastrocnemius wet weight ratio and sciatic function index. RESULTS AND CONCLUSION:(1)Compared with EVs-nor,EVs-prp was stronger in promoting Schwann cell proliferation.The gene expressions of c-Jun and GDNF were significantly upregulated in EVs-prp treated Schwann cells.The morphology of Schwann cells was significantly longer in EVs-prp group than that in EVs-nor group,indicating that EVs-prp had a stronger ability to stimulate Schwann cell reprogramming than EVs-nor.(2)Sciatic nerve injury animal experiment results revealed that grafting mesenchymal stem cells along with platelet-rich plasma into the injured sciatic nerve showed the best recovery compared with grafting mesenchymal stem cells or platelet-rich plasma alone,demonstrated by the significantly improved density of nerve fibers,gastrocnemius wet weight ratio,and sciatic function index.(3)These results suggested that platelet-rich plasma improved the function of bone marrow mesenchymal stem cell-derived extracellular vesicles and could be served as a practical and feasible preparation to synergize with bone marrow mesenchymal stem cells to improve peripheral nerve repair.

Efficient strategies for microglia replacement in spinal cord injury models / 中国组织工程研究

BACKGROUND:As the incidence of spinal cord injury increases with the years and axon regeneration after spinal cord injury was very difficult.How to promote the recovery from spinal cord injury and improve the transplantation efficiency of stem cells and other therapeutic cells after spinal cord injury has been the focus of clinical and scientific research. OBJECTIVE:To establish the efficient transplantation and replacement of mouse spinal cord microglia in the spinal cord injury model. METHODS:CX3CR1 creER-/+::LSL-BDNF-/+-tdTomato mice,CX3CR1+/GFP mice,β-actin GFP mice and C57 BL/6J wild-type mice at 8-10 weeks of age were selected.According to the requirements of the experiment,they were randomly divided into six groups.(1)Sham operation group:eight C57 BL/6J wild-type mice were used when only the lamina was removed without injury.(2)Spinal cord contusion injury group:eight C57 BL/6J wild-type mice were used.(3)Spinal cord crush injury group:eight C57 BL/6J wild-type mice were used.(4)Conjoined symbiotic spinal cord strike injury group:β-actin GFP mice with green fluorescent blood were surgically stitched together with C57 BL/6J wild-type mice,using eight β-actin GFP mice and eight C57 BL/6J wild-type mice.(5)Mr BMT-X Ray group(using PLX5622 to eliminate the spinal microglia and bone marrow transplantation with X-ray radiation):Bone marrow cells from four CX3CR1 creER-/+::LSL-BDNF-/+-tdTomato mice were extracted and transplanted into eight C57 BL/6J wild-type mice for spinal cord injury modeling.(6)Mr BMT-Busulfan group(using PLX5622 to eliminate the spinal microglia and bone marrow transplantation with Busulfan):Bone marrow cells from four CX3CR1+/GFP mice were transplanted into eight C57 BL/6J wild-type mice.The percentage of cell transplantation replacement in this group was observed,and the spinal cord injury model was not established in this group.The sham operation group,spinal cord contusion injury group and spinal cord crush injury group were sampled by perfusion on day 14 after spinal cord injury.The conjoined symbiotic spinal cord strike injury group was sampled by perfusion on day 7 after spinal cord injury.Mr BMT-X Ray group was sampled by perfusion on day 28 after spinal cord injury.Mr BMT-Busulfan group was sampled by perfusion on day 28 after transplantation.The sampling site was a 1.2 cm long spinal cord with the T10 segment as the center.In the Mr BMT-X Ray group and Mr BMT-Busulfan group,additional mouse brain tissue was retained to see if it would lead to brain transplantation and replacement.The number and proportion of transplanted and replaced cells in the damaged area were measured using transgenic mice,symbiosis and immunofluorescence. RESULTS AND CONCLUSION:Compared with the traditional peripheral blood transplantation(9.8%)of mice in the conjoined symbiotic spinal cord strike injury group,the new transplantation methods,Mr BMT-X Ray and Mr BMT-Busulfan,could greatly improve the proportion of spinal microglia transplantation and replacement,which could reach 84.8%and 95.6%,respectively.The difference was significant(P<0.05).The results showed that Mr BMT-X Ray and Mr BMT-Busulfan could achieve efficient replacement of spinal microglia cells,and could improve the problems of low cell transplantation efficiency,few survival numbers and unclear differentiation of the traditional cell transplantation methods.In addition,Mr BMT-X Ray can only replace the microglia in the spinal cord,while Mr BMT-Busulfan could avoid brain inflammation and injury caused by X-ray radiation transplantation.

Analysis of risk factors for short-term death after allogeneic hematopoietic stem cell transplantation / 中国组织工程研究

BACKGROUND:Allogeneic hematopoietic stem cell transplantation is an effective and even the only way to cure various hematological diseases,but the short-term mortality rate is relatively high after transplantation. OBJECTIVE:To investigate the risk factors affecting the overall survival of patients with hematological diseases in the short term(within 100 days)after allogeneic hematopoietic stem cell transplantation,so as to reduce mortality and effectively prevent related risks in the short term(within 100 days)after allogeneic hematopoietic stem cell transplantation. METHODS:Clinical data of 585 patients with hematological diseases who underwent allogeneic hematopoietic stem cell transplantation at the Hematopoietic Stem Cell Transplantation Center of First Affiliated Hospital of Zhengzhou University from January 1,2018 to June 30,2021 were retrospectively analyzed.The risk factors that affected overall survival within 100 days after allogeneic hematopoietic stem cell transplantation were explored. RESULTS AND CONCLUSION:A total of 585 patients with hematologic diseases underwent allogeneic hematopoietic stem cell transplantation.92 patients died within 100 days after transplantation,with a mortality rate of 15.7%(92/585).The median age of death cases was 26.5 years old(1-56 years),and the median survival time of death cases was 48 days(0-97 days).Univariate analysis exhibited that age≥14 years old,acute graft-versus-host disease,grade IV acute graft-versus-host disease,bacterial bloodstream infection,as well as carbapenem-resistant organism bloodstream infection,were risk factors for overall survival within 100 days after allogeneic hematopoietic stem cell transplantation(P<0.05).Multivariate regression analysis showed that age≥14 years old,grades Ⅲ-Ⅳ acute graft-versus-host disease,bacterial bloodstream infection,and carbapenem-resistant organism bloodstream infections were independent risk factors for overall survival(within 100 days)in patients after allogeneic hematopoietic stem cell transplantation.Hazard ratios were 1.77(95%CI 1.047-2.991),7.926(95%CI 3.763-16.695),2.039(95%CI 1.117-3.722),and 3.389(95%CI 1.563-7.347),respectively.In conclusion,all-cause mortality rate after allogeneic hematopoietic stem cell transplantation is relatively high in the short term.A timely diagnosis and effective treatment of bacterial bloodstream infection and acute graft-versus-host disease are essential to improving allogeneic hematopoietic stem cell transplantation outcomes.

Efficacy of umbilical cord mesenchymal stem cells replacing donor bone marrow cells in haploidentical hematopoietic stem cell transplantation / 中国组织工程研究

BACKGROUND:HLA haploid allogeneic hematopoietic stem cell transplantation provides a chance of survival for patients with high-risk hematologic malignancies.In recent years,the research on the transplantation mode and graft selection of haploidentical transplantation is still ongoing.At present,the mixed transplantation model of non-extracorporeal T-cell removal bone marrow and peripheral blood stem cells established by the Hematology Research Center of Peking University is gradually becoming popular in China,but this model requires the collection of donor bone marrow fluid,which increases the pain and risk of the donor. OBJECTIVE:To explore the curative effect of infusion of umbilical cord mesenchymal stem cells replacing donor bone marrow cells in haploidentical peripheral blood hematopoietic stem cell transplantation for malignant hematological diseases. METHODS:Fifty hematological malignancies patients who underwent haploidentical hematopoietic stem cell transplantation from January 2019 to May 2022 were selected and randomly assigned to two study groups at a ratio of 2:3.Among them,19 patients received umbilical cord mesenchymal stem cell combined with peripheral blood stem cell transplantation,and 31 patients were treated with bone marrow cells combined with peripheral blood stem cells.The study was approved by the Ethics Committee of Henan Provincial People's Hospital.The recipients of umbilical cord mesenchymal stem cells were first transfused with third-party umbilical cord mesenchymal stem cells(1×106/kg)on the day of transplantation,followed by peripheral blood hematopoietic stem cells 6 hours later.In the bone marrow group,donor bone marrow cells were transfused +1 day after transplantation and peripheral blood stem cells were transfused +2 days after transplantation.After transplantation,rabbit anti-human thymocyte immunoglobulin,cyclosporine A,mycophenolate mofetil,and a short-course methotrexate were used for graft-versus-host disease prophylaxis for all recipients. RESULTS AND CONCLUSION:No adverse events occurred during the reinfusion of umbilical cord mesenchymal stem cells.There were no significant differences between the mesenchymal stem cell group and the bone marrow group in the engraftment rate[100%(19/19)vs.96.8%(30/31),P>0.05],median duration for neutrophil engraftment(14 days vs.15 days,P>0.05)and median duration for platelet engraftment(20 days vs.19 days,P>0.05).The incidence of grade Ⅱ-Ⅳ acute graft-versus-host disease in the mesenchymal stem cell group was significantly lower than in the bone marrow group[21.1%(4/19)vs.58.1%(18/31),P = 0.01].There were no significant differences between the two groups in the incidence of chronic graft-versus-host disease[21.1%(4/19)vs.25.8%(8/31),P>0.05],the relapse rates[15.8%(3/19)vs.16.1%(5/31),P>0.05]and the incidence of early cytomegalovirus viremia[42.1%(8/19)vs.35.5%(11/31),P>0.05],and the 2-year overall survival rate[68.4%(10/19)vs.70.9%(16/31),P>0.05].It is indicated that umbilical cord mesenchymal stem cells replace donor bone marrow cells in haploidentical peripheral blood stem cell transplantation for malignant hematological diseases,which reduced the incidence of acute graft-versus-host disease after transplantation,did not increase the incidence of chronic graft-versus-host disease,recurrence rate and early cytomegalovirus viremia,and reduced the pain and risk of donor pulp extraction.

Strategies and advance on stem cell transplantation for repair of spinal cord injury / 中国组织工程研究

BACKGROUND:Spinal cord injury not only causes serious physical and psychological injuries to patients but also brings a heavy economic burden to society.Spinal cord injury is initially triggered by mechanical trauma,followed by secondary injuries,and as the disease progresses,a glial scar develops. OBJECTIVE:To summarize the pathological process of spinal cord injury and strategies for stem cell transplantation to repair spinal cord injury,aiming to provide the best protocol for treating spinal cord injury. METHODS:Computer search was used to search PubMed and CNKI databases.Chinese search terms were"stem cell transplantation,spinal cord injury".English search terms were"stem cell,spinal cord injury,spinal cord,mesenchymal stem cells,neural stem cells,pathophysiology,clinical trial,primary injury,secondary injury".The literature was screened according to the inclusion and exclusion criteria.Finally,91 articles were included for review analysis. RESULTS AND CONCLUSION:(1)The strategies for repairing spinal cord injury through stem cell transplantation can be divided into exogenous stem cell transplantation and endogenous stem cell transplantation.The exogenous stem cell transplantation strategy for the treatment of spinal cord injury is divided into four kinds:injecting stem cells into the site of injury;transplantation of biomaterials loaded with stem cells;fetal tissue transplantation;transplantation of engineered neural network tissue or spinal cord-like tissue.(2)Compared with a single treatment method,combination therapy can more effectively promote nerve regeneration and spinal cord function recovery.(3)Microenvironment regulating the injury site,magnetic stimulation,electrical stimulation,epidural oscillating electric field stimulation,transcription factor overexpression and rehabilitation therapy can be combined with stem cell transplantation for combination therapy,thereby promoting the recovery of spinal cord function.

Neuron-derived extracellular vesicles promote neurogenesis of neural stem cells / 中国组织工程研究

BACKGROUND:It has been shown that neural stem cells can differentiate into neurons,astrocytes,and oligodendrocytes.Mesenchymal stem cells-derived extracellular vesicles have also been shown to cross the blood-brain barrier to reach sites of central nervous injury and promote neural repair.However,it is not clear whether neuron-derived extracellular vesicles promote the differentiation of neural stem cells in a direction that is beneficial for neurogenesis. OBJECTIVE:To investigate whether neuron-derived extracellular vesicles facilitate neural stem cell differentiation towards neurogenesis. METHODS:Neurons and neural stem cells were extracted from neonatal SD rat cerebral cortex by trypsin digestion.Cell supernatants of neurons were collected.Neuron-derived extracellular vesicles were extracted.Neural stem cells cultured for 10 days were co-cultured with neuron-derived extracellular vesicles or PBS for 7 days.Immunoblotting,immunofluorescence,and RT-qPCR were used to detect proteins specifically expressed by neurons,neural stem cells,oligodendrocytes,and astrocytes. RESULTS AND CONCLUSION:The neural stem cells co-cultured with neuron-derived extracellular vesicles showed high expression of neuron-specific proteins and oligodendrocyte-specific proteins including β3-tubulin,neurofilament 200 and myelin basic protein,and low expression of astrocyte-specific protein glial fibrillary acidic protein.These results suggest that neuron-derived extracellular vesicles can promote the differentiation of neural stem cells into neurons and oligodendrocytes and prevent the differentiation of neural stem cells into astrocytes.