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

• 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
• 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

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 造血茎和祖细胞（HSPC）移植（HSCT）通常用于 治疗先天错误。离体基因编辑/治疗已成为成功治疗的工具 骨髓（BM）衰竭（BMF）和免疫缺陷的患者。但是，完整 这些患者的HSC植入需要大于预期的细胞剂量和HSC移植 可用于改善骨骼疾病，例如成骨症Imperfecta。这些意外的观察 尚未进行严格的机理分析。 线粒体是桥接转录特征和细胞的众所周知的代谢传感器 功能。 HSC的线粒体含量升高，但优先使用糖酵解和低 大量实验数据支持的HSC中的线粒体活性表明 线粒体呼吸对HSC比其细胞后代更具性能。 我们的初步数据表明，线粒体转移存在于造血细胞及其之间 周围的微环境，对造血和间充质的功能后果 骨髓化后的再生。我们的数据表明存在 线粒体命运定义了通过 由两个主要分子淋巴结控制的代谢耦合。我们假设HSPC线粒体 转移是BM的HSPC和MSC/P之间的代谢耦合所必需的。目标的目标 建议是定义控制线粒体含量并从转移的机制 造血植入细胞及其对BM间充质再生的影响。我们将阐明 BM生态位线粒体转移的机制及其使用遗传和使用的功能相关性 获得和丧失功能和枚举和功能分析的药理工具 线粒体在HSC利基市场中的生化后果。线粒体转移 重新编程受体BM MSC/P的代谢组，此重编程是必要的 BM和骨的间充质细分市场的间充质增殖和重建 骨髓化后BM的再生。我们将确定a）负调节剂的角色 线粒体转移中的CX43取决于细胞间接触。 b）从BM的线粒体转移 HSPC至BM MSC/P诱导间充质微环境的代谢重编程 导致造血再生；并且，c）BM需要预防AMPK激活 间充质和造血再生。该提案将提供有关分子基础的灯 移植后造血依赖性间充质再生，并将确定 造血CX43和宿主AMPK活性在骨髓代谢耦合上。