Age-related Responses of Epidermal Stem Cells to Environ

表皮干细胞对环境的年龄相关反应

基本信息

批准号：
7035837
负责人：
JACKIE R BICKENBACH
金额：
$ 21.61万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2007-03-31
项目状态：
已结题

项目摘要

Homeostasis of continuously renewing tissues, such as the epidermis, is maintained by somatic stem cells. These are undifferentiated, self-renewing cells, which also produce daughter transient amplifying (TA) cells that make up the majority of the proliferative population. TA cells undergo a finite number of cell divisions before leaving the proliferative compartment and moving toward terminal differentiation, whereas it has been assumed that the stem cells persist throughout the lifetime of the organism. Through a series of labeling experiments with tritiated thymidine, we previously showed that stem cells from adult mouse skin did not divide as often as the other basal cells, but they did divide at a steady rate in vivo. We also showed that they continued to proliferate in vivo throughout life, and that they have a high proliferative potential in vitro. Thus, it may be that epidermal stem cells do not follow the Hayflick theory and possibly "live forever." Last year, we developed a sorting method that yields a viable population of stem cells from the epidermis. We showed that these stem cells have the capacity to regenerate the epidermis and to continuously express a recombinant gene in the regenerated tissue. Thus, they are the stem cells for the epidermis. Very recently, we determined that these epidermal stem cells also have the remarkable ability to participate in the formation of the other tissues, a plasticity similar to that of embryonic stem cells and a few other somatic stem cells. Our preliminary data show that the epidermal stem cells isolated from neonatal mouse skin incorporate into a variety of tissues and alter their phenotype after injection into blastocysts. Thus, the fate determination of these stem cells appears to be in direct response to their environment. We also determined that the cell cycle profile of these cells appears to be an intrinsic property of the stem cell and not related to the age of the cell. These data have led us to ask what happens to epidermal stem cells as the organism ages? In this application, we propose to test whether the age of the stem cells has an effect on its response to the environment or extrinsic factors in determining its fate pathway. We propose the following specific aims: 1) to compare old vs. young murine epidermal stem cells by determining their number, altered phenotype and longevity after injection into blastocysts, and to determine whether there is a difference in the life span of mice derived from blastocysts injected with old vs. young stem cells; and 2) to compare old vs. young adult human epidermal stem cells by determining if there is a difference in their in vitro growth potential and if they respond differently to extrinsic environmental signals in vitro and after injection into blastocysts.

诸如表皮等连续更新组织的稳态由体细胞维持。这些是未分化的自我更新细胞，还产生构成大多数增殖种群的女儿瞬态扩增（TA）细胞。 TA细胞在离开增殖室并向终末分化之前进行有限数量的细胞分裂，而已假定干细胞在生物体的整个生命周期中持续存在。通过一系列对胸腺胺的标记实验，我们先前表明，成年小鼠皮肤的干细胞的分裂不如其他基底细胞分裂，但它们确实在体内以稳定的速率分裂。我们还表明，它们在整个生命中继续在体内增殖，并且在体外具有很高的增殖潜力。因此，表皮干细胞可能不遵循干草理论，而是“永远生存”。去年，我们开发了一种分类方法，该方法产生了表皮的可行干细胞群体。我们表明，这些干细胞具有再生表皮并在再生组织中连续表达重组基因。因此，它们是表皮的干细胞。最近，我们确定这些表皮干细胞还具有参与其他组织形成的能力，可塑性类似于胚胎干细胞和其他一些其他体细胞细胞。我们的初步数据表明，从新生小鼠皮肤中分离出的表皮干细胞会融合到各种组织中，并在注射到胚泡中后改变其表型。因此，这些干细胞的命运确定似乎对其环境直接反应。我们还确定这些细胞的细胞周期谱似乎是干细胞的固有特性，并且与细胞的年龄无关。这些数据导致我们问表皮干细胞随着生物年龄的变化会发生什么？在此应用中，我们建议测试干细胞的年龄是否对确定其命运途径的环境或外在因素的反应有影响。我们提出以下具体目的：1）通过确定注射到胚泡后的数量，改变表型和寿命的数量，改变表型和寿命，并确定从注射旧囊肿的小鼠寿命差异，以比较旧鼠表皮干细胞的寿命差异； 2）通过确定其体外生长潜力是否有差异，以及它们在体外和注射到胚泡后对外在环境信号的反应不同，以比较旧的成年人表皮干细胞。