Fetal Stromal Progenitor Cells

描述(由申请人提供)： 我们目前对间充质干细胞(MSC)生物学的大部分知识来自于成人组织来源。MSC生物学的发育方面仍然相对未知。然而，了解MSC样群体的个体发育及其在正常发育中的作用可能会为MSCs的出生后鉴定、功能表征以及最终的临床应用提供重要的见解。这项应用的长期目标是将从分离、表征和分析产前间充质干细胞群体中获得的见解应用于开发临床有用的出生后MSC群体的目标。这项应用的具体目的是：1)在小鼠模型中完成胎儿多潜能基质祖细胞群体的体外鉴定。我们已经从胎肝、胎骨髓和脐带血中分离并鉴定了独特的小鼠多能基质祖细胞(FMSP)群体。我们假设发育中的胎儿在多个组织中存在一个共同的fMSP。为了达到这一目标，我们将对每个fMSP群体进行全面的表征，并在体外生长特性、克隆扩增、多能性、支持造血的能力以及胚胎细胞标记的表达方面进行比较。2)明确小鼠多能基质祖细胞的发育个体发育。我们假设fMSPs在胎儿中有一个共同的起源部位，并在发育过程中迁移到造血和非造血组织。为了解决这一假设，我们将尝试从胎儿特定的造血区和非造血区分离出fMSPs，在Aorto-性腺-中肾区、胎肝和胎儿骨髓的造血术开始之前和同时进行。3)在小鼠子宫内干细胞移植模型中对胎儿多能基质祖细胞进行体内评价。我们将使用我们实验室开发的腹膜内或血管内胎儿注射技术，将优化的转基因GFP/男性fMSP群体移植到胎儿受体体内。我们将在相对不受干扰的胎儿模型环境中研究fMSPs的归巢、短期和长期植入以及体内多潜能。这些研究将提高我们对间充质祖细胞发育生物学的了解，并有助于更好地了解它们在正常组织重塑和成熟过程中的生理作用，以及最终它们在应对损伤或疾病的组织修复和再生中扮演的角色(如果有的话)。

DESCRIPTION (provided by applicant): Most of our current knowledge of mesenchymal stem cell (MSC) biology derives from adult tissue sources. The developmental aspects of MSC biology remain relatively unknown. Yet it is likely that understanding the ontogeny of MSC like populations and their role in normal development can provide important insights toward the postnatal identification, functional characterization, and ultimately the clinical utilization of MSCs. The long-term objective of this application is to apply insights gained from the isolation, characterization, and analysis of prenatal mesenchymal progenitor populations toward the goal of developing clinically useful postnatal MSC populations. The specific aims of this application are: 1) To complete the in vitro characterization of fetal multipotent stromal progenitor populations in the murine model. We have isolated and begun to characterize unique populations of murine fetal multipotent stromal progenitor (fMSP) cells from fetal liver, fetal bone marrow, and cord blood. We hypothesize that a common fMSP exists in the developing fetus in multiple tissues. In this aim, each fMSP population will be fully characterized and compared with respect to in vitro growth characteristics, clonal expansion, multipotentiality, ability to support hematopoiesis, and expression of embryonal cell markers. 2) To define the developmental ontogeny of murine multipotent stromal progenitors. We hypothesize that fMSPs have a common site of origin in the fetus and migrate to hematopoietic and non-hematopoeitic tissues during development. To address this hypothesis, we will attempt to isolate fMSPs from specific hematopoietic and non-hematopoietic regions of the fetus prior to, and concurrent with, onset of hematopoiesis in the Aorto-Gonadal-Mesonephric region, fetal liver, and fetal bone marrow. 3) To assess fetal multipotent stromal progenitors in vivo in the murine in utero stem cell transplantation model. We will transplant optimized populations of transgenic GFP/male fMSPs into fetal recipients using techniques developed by our laboratory for intraperitoneal, or intravascular fetal injection. We will investigate homing, short and long term engraftment, and in vivo multipotentiality of fMSPs in the relatively unperturbed milieu of the fetal model. These studies should improve our understanding of the developmental biology of mesenchymal progenitors and should lead to a better understanding of their physiologic role in normal tissue remodeling and maturation and ultimately, what role, if any, they play in tissue repair and regeneration in response to injury or disease.