Potten C S, Martin K, Kirkwood T B
Epithelial Biology Department, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX.
Novartis Found Symp. 2001;235:66-79; discussion 79-84, 101-4. doi: 10.1002/0470868694.ch7.
Most organs of the body comprise populations of cells that are committed to specialized functions and that are renewed from small numbers of uncommitted progenitor or 'stem' cells. Stem cells are of central importance in the study of ageing because any senescent decline in the number or functional competence of stem cells will impair the capacity for renewal and turnover of committed cells, with potentially serious consequences for tissue homeostasis. The intestinal epithelium represents an excellent model system for the study of stem cells. Its spatial and hierarchical organisation allows the study of the function or characteristic of a given cell according to its position within the crypt. Hence, the stem cells which are located at the 4th-5th cell position from the bottom can be studied together with their daughter cells, as they divide and differentiate while migrating along the crypt-villus axis. The ability of the stem cells to undergo apoptosis and the capacity to regenerate the epithelium following injury were investigated in mice of different ages. Stem cells from older animals showed an increased apoptotic response following exposure to low doses of ionising radiation. The regenerative capacity was estimated by measuring the crypt survival levels and the growth rate of surviving crypts after high doses of irradiation. Surviving crypts in the older mice, suggesting an impairment in the damage recognition/response mechanisms, were both fewer and smaller than in young mice. The growth rate of surviving crypts was determined by measuring the crypt area and the number of cells/crypt at various times after 14 Gy irradiation. There was a growth delay of between half and one day in the older mice, and they subsequently grew more slowly. The number of cells susceptible to regenerate a crypt was also estimated. Surprisingly, they appear to be more numerous in the older mice. These studies indicate important age-related alterations in the capacity of the stem cells to regenerate the crypts after radiation-induced damage. The molecular bases of these changes are currently being investigated. Preliminary data showed alteration in the level of p53 and p21 expression, suggesting an age-related defect in the capacity to recognize damage and initiate apoptosis or repair.
身体的大多数器官都由致力于特定功能的细胞群组成，这些细胞群由少量未分化的祖细胞或“干细胞”更新而来。干细胞在衰老研究中至关重要，因为干细胞数量或功能能力的任何衰老性下降都会损害分化细胞的更新和更替能力，对组织稳态产生潜在的严重后果。肠上皮是研究干细胞的一个极佳模型系统。其空间和层次组织允许根据细胞在隐窝内的位置研究给定细胞的功能或特征。因此，位于隐窝底部第4 - 5个细胞位置的干细胞及其子代细胞可以一起研究，因为它们在沿隐窝 - 绒毛轴迁移时进行分裂和分化。在不同年龄的小鼠中研究了干细胞发生凋亡的能力以及损伤后上皮再生的能力。老年动物的干细胞在暴露于低剂量电离辐射后显示出增加的凋亡反应。通过测量高剂量辐射后隐窝存活水平和存活隐窝的生长速率来评估再生能力。老年小鼠中存活的隐窝数量和大小均少于年轻小鼠，这表明损伤识别/反应机制受损。通过测量14 Gy辐射后不同时间的隐窝面积和每个隐窝的细胞数量来确定存活隐窝的生长速率。老年小鼠有半天到一天的生长延迟，随后生长更慢。还估计了能够再生一个隐窝的细胞数量。令人惊讶的是，老年小鼠中的这类细胞似乎更多。这些研究表明，辐射诱导损伤后干细胞再生隐窝的能力存在重要的年龄相关变化。目前正在研究这些变化的分子基础。初步数据显示p53和p21表达水平发生改变，表明在识别损伤并启动凋亡或修复的能力方面存在年龄相关缺陷。
