Telomerase as a Marker of Brown and White Adipose Tissue Stem Cells

描述(申请人提供)：脂肪组织基质血管成分(SVF)是一种多潜能间充质干细胞的来源，可从棕色和白色脂肪组织中分离出来。虽然人们已经接受了SVF中存在产生成熟脂肪组织的前体细胞的观点，但能够自我更新的多潜能脂肪干细胞还没有得到分子上的定义。我们的初步数据显示，小鼠端粒酶逆转录酶表达(MTert)标志着一群棕色和白色的脂肪SVF细胞，它们在体外表达能够自我更新和成脂分化的假定的成脂前体细胞表面标志。此外，从3周到6月龄，体内棕色和白色脂肪组织中的mTert细胞谱系处于静止状态，但高脂饮食导致8月龄动物mTert谱系的增殖增加。基于这些发现，该项目旨在测试新的假设，即mTert表达细胞是多潜能脂肪干细胞，能够对高脂肪饮食和作为分化线索的β-肾上腺素能刺激做出反应。该研究有两个特定的目的：1)体外对mTert表达细胞的功能和分子特征进行鉴定，比较这些可能的脂肪干细胞和定向祖细胞；2)确定分化信号对mTert细胞增殖和分化的影响，并在体内与PDGFRα-CreerT2小鼠的定向祖细胞进行比较。鉴定脂肪组织干细胞及其增殖和分化的调控机制将对理解脂肪组织发育和肥胖具有重要意义，这一认识可能适用于人类疾病或损伤的自体组织移植。

DESCRIPTION (provided by applicant): Adipose tissue stromal vascular fraction (SVF) is a source of multipotent mesenchymal stem cells that can be isolated from brown and white adipose tissue. While it is accepted that the precursor cells that give rise to mature adipose tissue reside in the SVF, multipotent adipose stem cells capable of self-renewal have not been molecularly defined. Our preliminary data show that mouse telomerase reverse transcriptase expression (mTert) marks a population of brown and white adipose SVF cells expressing putative adipogenic precursor cell surface markers that are capable of self-renewal and adipogenic differentiation in vitro. Further, the mTert cellular lineage is quiescent in brown and white adipose tissue in vivo from 3 weeks of age until 6 months, however high fat diet caused an increase in mTert lineage proliferation in 8-month old animals. Based on these findings, this project is designed to test the novel hypothesis that mTert expressing cells are multipotent adipose stem cells capable of responding to high fat diet and beta-adrenergic stimulation that serve as differentiation cues. There are two specific aims: 1) Functional and molecular characterization of mTert- expressing cells in vitro comparing these putative adipose stem cells to committed progenitor cells; 2) Determine the effects of differentiation cues on mTert cell proliferation and differentiation in adipose in vivo compared to committed progenitor cells from PDGFrα-CreERT2 mice. Identifying adipose tissue stem cells and the mechanisms that govern their proliferation and differentiation will have important significance in the understanding of adipose tissue development and obesity and this knowledge may be applicable in autologous tissue transplants in human disease or injury.