Mitochondria mediated intercellular metabolic coupling in bone marrow regeneration

线粒体介导骨髓再生中的细胞间代谢耦合

基本信息

批准号：
10198919
负责人：
Jose A Cancelas
金额：
$ 27.98万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198919
关键词：
Biochemical Biology Bone Diseases Bone Marrow Bone Marrow Purging Bone Regeneration Bone Tissue Cell physiology Cells Clinical Clinical Data Connexin 43 Connexins Coupling Data Data Set Disease Dose Engineering Engraftment Gene Expression Profile Genetic Glycolysis Goals Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Hereditary Disease Homeostasis Immunologic Deficiency Syndromes In Vitro Laboratories Light Mediating Mesenchymal Mesenchymal Stem Cells Metabolic Mitochondria Molecular Mutation Natural regeneration Osteogenesis Imperfecta PDGFRB gene Pancytopenia Patients Pharmacology Prevention Property Radiation therapy Recovery Regulation Respiration Role Signal Transduction Stem cell transplant Therapeutic Transplantation Work bone bone cell bone marrow mesenchymal stem cell chemoradiation cohort hematopoietic stem cell niche in vivo intercellular communication loss of function metabolic fitness metabolome oxidative damage post-transplant prevent progenitor reconstitution regenerative sensor stem cells therapeutic genome editing tool translational approach

项目摘要

ABSTRACT Hematopoietic stem and progenitor cell (HSPC) transplantation (HSCT) is routinely used for the treatment of inborn errors. Ex vivo gene editing/therapy is becoming a successful tool for treatment of patients with bone marrow (BM) failure (BMF) and immunodeficiencies. However, the complete engraftment of HSC in these patients requires larger-than-expected cell doses and HSC transplantation is useful in ameliorating bone diseases like osteogenesis imperfecta. These unexpected observations have not been followed by a stringent mechanistic analysis. Mitochondria are well known metabolic sensors that bridge transcriptional signatures and cellular functions. The mitochondrial content of HSC is elevated but the preferential use of glycolysis and low mitochondrial activity in HSC as supported by a large cohort of experimental data suggest that mitochondrial respiration is more dispensable for HSC than for their cell progeny. Our preliminary data indicate that mitochondrial transfer exists between hematopoietic cells and their surrounding microenvironment with functional consequences on hematopoietic and mesenchymal regeneration after myeloablation. Our data suggests the existence of refined configuration of the mitochondrial fate defining the HSC and microenvironment fate in the regenerating bone marrow by metabolic coupling controlled by two major molecular nodes. We hypothesize that HSPC mitochondria transfer is required for metabolic coupling between HSPC and MSC/P of the BM. The goal of this proposal is to define the mechanisms that control the mitochondrial content and transfer from hematopoietic engrafting cells and their impact on BM mesenchymal regeneration. We will elucidate the mechanisms of mitochondrial transfer in the BM niche and their functional relevance using genetic and pharmacological tools of gain- and loss-of-function and enumeration and functional analysis of biochemical consequences of the traffic of mitochondria in the HSC niche. The mitochondrial transfer reprograms the metabolome of recipient BM MSC/P and this reprogramming is necessary for mesenchymal proliferation and reconstitution of the mesenchymal niche of the BM as well as bone regeneration of the BM after myeloablation. We will determine whether a) the negative regulator role of Cx43 in mitochondrial transfer depends on cell-to-cell contact; b) the mitochondrial transfer from BM HSPC to BM MSC/P induces metabolic reprogramming of the mesenchymal microenvironment resulting in hematopoietic regeneration; and, c) the prevention of AMPK activation is required for BM mesenchymal and hematopoietic regeneration. This proposal will provide light on the molecular basis of hematopoietic-dependent mesenchymal regeneration after transplantation and will identify the role of hematopoietic Cx43 and host AMPK activity on bone marrow metabolic coupling.

抽象的造血干细胞和祖细胞（HSPC）移植（HSCT）通常用于先天性错误的治疗。离体基因编辑/疗法正在成为治疗以下疾病的成功工具患有骨髓（BM）衰竭（BMF）和免疫缺陷的患者。然而，完整的这些患者的 HSC 植入需要高于预期的细胞剂量和 HSC 移植可用于改善成骨不全等骨骼疾病。这些意想不到的观察结果尚未进行严格的机制分析。线粒体是众所周知的代谢传感器，可桥接转录特征和细胞功能。 HSC的线粒体含量升高，但优先使用糖酵解且低大量实验数据支持的 HSC 线粒体活性表明线粒体呼吸对于 HSC 而言比其子代细胞更可有可无。我们的初步数据表明，造血细胞与其细胞之间存在线粒体转移。周围微环境对造血和间充质的功能影响骨髓清除后的再生。我们的数据表明存在精细配置线粒体命运定义了再生骨髓中 HSC 和微环境的命运由两个主要分子节点控制的代谢耦合。我们假设 HSPC 线粒体 HSPC 和 BM 的 MSC/P 之间的代谢耦合需要转移。此举的目标建议是定义控制线粒体内容和转移的机制造血移植细胞及其对骨髓间充质再生的影响。我们将阐明 BM 生态位中线粒体转移的机制及其使用遗传和功能的相关性功能获得和丧失的药理学工具以及计数和功能分析 HSC 生态位中线粒体运输的生化后果。线粒体转移重新编程受体 BM MSC/P 的代谢组，这种重新编程对于骨髓和骨的间充质增殖和间充质生态位的重建清髓后 BM 的再生。我们将确定 a) 是否具有负调节作用线粒体转移中的 Cx43 取决于细胞间的接触； b) 来自 BM 的线粒体转移 HSPC 转化为 BM MSC/P 诱导间充质微环境代谢重编程导致造血再生； c) BM 需要防止 AMPK 激活间充质和造血再生。该提案将为分子基础提供线索移植后造血依赖性间充质再生并确定其作用造血 Cx43 和宿主 AMPK 活性对骨髓代谢的耦合作用。