Genes, cells, and pathways that regulate urochordate allogeneic stem cell competition and their mammalian homologues

调节尾索动物同种异体干细胞竞争及其哺乳动物同源物的基因、细胞和途径

• 批准号: 9056061
• 负责人: IRVING L. WEISSMAN
• 金额: $ 35.08万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9056061
• 关键词: Activities of Daily Living; Affect; Aging; Alleles; Allogenic; Anastomosis - action; Animal Model; Bioinformatics; Biological; Blood; Blood Vessels; Bone Marrow Transplantation; Candidate Disease Gene; Cell physiology; Cells; Cessation of life; Chimera organism; Chimerism; Chordata; Competence; Development; Engraftment; Exhibits; Failure; Fertility; Figs - dietary; Gene Expression; Genes; Genetic; Genetic Determinism; Genomics; Genotype; Germ; Germ Lines; Gonadal structure; Graft Rejection; Hematological Disease; Hematopoiesis; Hematopoietic stem cells; Homologous Gene; Human; Immune response; Individual; Inherited; Mammals; Mediating; Medical; Modeling; Molecular; Molecular Profiling; Mus; Natural regeneration; Occupations; Organogenesis; Outcome; Pancytopenia; Pathway interactions; Patients; Research; Seeds; Signal Pathway; Staging; Stem cell transplant; Stem cells; Technology; Testing; Testis; Tissues; Translating; Transplantation; Urochordata; Work; asexual; base; design; disorder later incidence prevention; gene discovery; genetic variant; germline stem cells; hematopoietic cell transplantation; high risk; improved; in vivo; insight; knock-down; leukemia; meetings; neuronal cell body; next generation; novel; public health relevance; stem cell biology; trait; transcriptome sequencing; transplantation medicine

 DESCRIPTION (provided by applicant): Allogeneic hematopoietic cell transplantation (HCT) is used for patients with high-risk leukemias and bone marrow failure. In HCT, complete donor hematopoiesis is essential for sustained engraftment and prevention of relapse. In the post-transplant setting, clonal preleukemic precursors can re-emerge. In human AML, clonal preleukemic progression occurs in the hematopoietic stem cell [HSC] stage, and each heritable change increases the competitive competence of the clone vs normal HSC. We tested for mammalian germline stem cell competitions, for HSC competitions in aging, and in the progression of competitive HSC in human leukemias based on our early studies of stem cell competitions for germline and soma niches in the colonial chordate Botryllus schlosseri. B. schlosseri is an urochordate model organism that exhibits natural stem-cell mediated chimerism, and shares stem-cell associated gene sets and pathways with human and mouse. When two genetically distinct colonies meet, they either anastomose extracorporeal blood vessels to form a chimera with a common vasculature, or reject one another. In some chimeras, one of the chimeric partners undergoes partial or complete reabsorption. Circulating germ and/or somatic stem cells of one partner in a chimera can compete with and replace the germ line and/or soma of the other partner. Stem cell engraftment in B. schlosseri is regulated on four different levels: 1). fusion or rejection; 2). if fusion occurs, the body of the losing partner is resorbed; 3). competition between circulating somatic stem cells to seed buds for asexual whole body development; and 4). stem cell competition among germ line stem cells, which determines the genotype of the next generation. We discovered the gene (BHF) that controls fusion/rejection, and found that the other levels are also heritable. Thus, genetically distinct strains have somatic stem cells that, in a chimera, vary in their vulnerability to be resorbed, undergo competitions to "win" or "lose" differentiated tissue [akin to regeneration], and to win or lose germline niches. Each level of stem cell competition has biological and medical implications: resorption is a model for stem cell loss (failure to bud); somatic competitions relat to stem cell transplant engraftability, and germline stem cell competition determines which genotypes are inherited (fertility). To discover genes and key pathways that regulate stem cell functionality and engraftment potential, we established genetically distinct B. schlosseri strains with different levels of engraftment potential (the ability to not be resorbed in a chimera and/or o win in stem cell competition), sequenced their tissue specific RNAs, and analyzed their gene expression profiles. We arrived at a list of candidate genes and pathways that most likely alter stem cell competitive potential. We will use gene knockdown technology to assess the function of different genes in migrating stem cells in vivo that participate in organogenesis and gonad development. Eventually we will test whether these pathways regulate HSC competitions in allogeneic transplants.

 描述(申请人提供)：异基因造血细胞移植(HCT)用于高危白血病和骨髓衰竭患者。在HCT中，完全的供者造血对于持续植入和防止复发是必不可少的。在移植后的环境中，克隆性白血病前体可以重新出现。在人类AML中，克隆性白血病前期进展发生在造血干细胞[HSC]阶段，每个可遗传的变化都会增加克隆与正常HSC的竞争能力。我们基于我们早期在集群脊索动物Botryllus schlosseri中对生殖系和胞体生态位的干细胞竞争的研究，测试了哺乳动物生殖系干细胞竞争、衰老中的HSC竞争以及人类白血病中竞争性HSC的进展。施洛瑟氏杆菌是一种尿索模式生物，表现出天然的干细胞介导的嵌合体，并与人类和小鼠共享干细胞相关基因集和途径。当两个遗传上截然不同的群体相遇时，它们要么与体外血管吻合，形成与共同血管系统的嵌合体，要么相互排斥。在一些嵌合体中，其中一个嵌合伙伴经历部分或完全的重吸收。嵌合体中一个伴侣的循环生殖细胞和/或体细胞可以与另一个伴侣的生殖系和/或胞体竞争并取代。干细胞在Schlosseri体内的植入受到四个不同水平的调控：1)。融合或排斥；2)。如果发生融合，失去伴侣的身体被吸收；3)循环中的体细胞干细胞与种子芽竞争以促进全身无性发育；4)生殖系干细胞之间的干细胞竞争，这决定了下一代的基因。我们发现了控制融合/排斥的基因(BHF)，并发现其他水平也是可遗传的。因此，在基因上不同的菌株拥有体细胞干细胞，在嵌合体中，这些干细胞在被吸收的易感性上有所不同，它们经历了“赢”或“输”分化组织[类似于再生]的竞争，以及赢得或 失去生殖系的利基。每一级别的干细胞竞争都有生物学和医学意义：吸收是干细胞丢失(不能发芽)的模型；体细胞竞争与干细胞移植的可植入性有关，生殖系干细胞竞争决定了哪些基因类型是遗传的(生育)。为了发现调控干细胞功能和植入潜力的基因和关键途径，我们建立了不同水平的植入潜力(不被嵌合体吸收和/或在干细胞竞争中获胜的能力)的不同斯氏杆菌菌株，对它们的组织特异性RNA进行了测序，并分析了它们的基因表达谱。我们得出了一个候选基因和途径的清单，这些基因和途径最有可能改变干细胞的竞争潜力。我们将使用基因敲除技术来评估体内参与器官发生和性腺发育的移行干细胞中不同基因的功能。最终，我们将测试这些途径是否调节同种异体移植中的HSC竞争。