Stem Cell Lineage Selection in a Protochordate

描述(申请人提供)：所有多细胞生物起源于一小组全能的胚胎干细胞，这些干细胞扩展并分化为成熟个体的组织和器官。然而，个体并不是静止的实体，在正常的生长和衰老过程中，或在受伤后，分化的细胞、组织和器官必须得到补充和再生。在成人中，这种再生过程被认为是由干细胞或祖细胞进行的，这些干细胞或祖细胞在个体的整个生命周期中保持着扩张和分化的能力。然而，这些细胞的性质以及控制其增殖和分化的细胞和分子机制尚不清楚，但具有重要的临床意义。使用模型系统，提供实验上可获得的可靠的再生潜力，可以帮助我们理解再生背后的生物学原理。这项提案的总体目标是从原始脊索动物Botryllus schlosseri中分离和鉴定干细胞。施洛瑟氏杆菌为研究干细胞生物学提供了一个独特的模型，原因有两个。首先，再生是Botryllus生活史的重要组成部分：在高度协调的发育过程中，Botryllus成虫每周都会再生自己，包括所有的体细胞组织和生殖系。其次，在自然条件下，负责这种再生的细胞可以在两个人之间动员和移植。一旦被移植，这些细胞就可以增殖并超越竞争宿主干细胞，并在胚系水平和胞体中独立地接管另一个个体，在宿主的剩余寿命中，这两个过程分别被称为生殖系细胞寄生(GCP)或体细胞寄生(SCP)，我们已经证明了这个过程是有遗传基础的。干细胞生物学的基本、保守和重要的方面，如自我更新能力、归巢或扩增和分化动力学，必须是一种基因型的干细胞与另一种基因型的干细胞竞争的能力的基础。这项建议的总体目标是使用该系统前瞻性地分离负责GCP和SCP的细胞(S)，确定这些细胞(S)的细胞和分子生物学表型，并将这些表型与寄生能力相关联。

DESCRIPTION (provided by applicant): All multicellular organisms originate from a small set of totipotent embryonic stem cells which expand and differentiate into tissues and organs of a mature individual. However, individuals are not static entities, and during normal growth and aging, or after injury, differentiated cells, tissues and organs must be replenished and regenerated. In adults, this process of regeneration is thought to be carried out by stem or progenitor cells which retain the capacity to expand and differentiate throughout the lifespan of the individual. However, the nature of these cells and the cellular and molecular mechanisms which control their expansion and differentiation are not well-understood, but have important clinical significance. Using model systems that provide experimentally accessible and reliable regenerative potential can facilitate our understanding of the biology underlying regeneration. The overall objectives of this proposal are designed to isolate and characterize stem cells from the primitive chordate, Botryllus schlosseri. B. schlosseri provides a unique model to study stem cell biology for two reasons. First, regeneration is a major part of the life history of Botryllus: in a highly coordinated developmental process, Botryllus adults regenerate themselves, including all somatic tissues and the germline, every week. Secondly, under natural conditions the cells responsible for this regeneration can mobilize and transplant between two individuals. Once transplanted, these cells can proliferate and out compete host stem cells and take over the other individual independently at the level of the germline and in the soma for the remaining lifetime of the host, in processes called germline cell parasitism (gcp) or somatic cell parasitism (scp), respectively, and we have shown that there is a genetic basis to this process. Fundamental, conserved and important aspects of stem cell biology, such as self- renewal capacity, homing or expansion and differentiation kinetics must underlie the ability of a stem cell of one genotype to out compete a stem cell of another genotype. The overall goals of this proposal are to use this system to prospectively isolate the cell(s) responsible for gcp and scp, determine the cellular and molecular biological phenotype of these cell(s), and correlate those phenotypes with parasitic capability.