Department of Stem Cell and Regenerative Biology, Harvard University, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02115, USA.
Nature. 2010 Jan 28;463(7280):495-500. doi: 10.1038/nature08749.
Ageing in multicellular organisms typically involves a progressive decline in cell replacement and repair processes, resulting in several physiological deficiencies, including inefficient muscle repair, reduced bone mass, and dysregulation of blood formation (haematopoiesis). Although defects in tissue-resident stem cells clearly contribute to these phenotypes, it is unclear to what extent they reflect stem cell intrinsic alterations or age-related changes in the stem cell supportive microenvironment, or niche. Here, using complementary in vivo and in vitro heterochronic models, we show that age-associated changes in stem cell supportive niche cells deregulate normal haematopoiesis by causing haematopoietic stem cell dysfunction. Furthermore, we find that age-dependent defects in niche cells are systemically regulated and can be reversed by exposure to a young circulation or by neutralization of the conserved longevity regulator, insulin-like growth factor-1, in the marrow microenvironment. Together, these results show a new and critical role for local and systemic factors in signalling age-related haematopoietic decline, and highlight a new model in which blood-borne factors in aged animals act through local niche cells to induce age-dependent disruption of stem cell function.
在多细胞生物中，衰老通常涉及细胞替换和修复过程的逐渐衰退，导致多种生理缺陷，包括肌肉修复效率降低、骨量减少以及血液形成（造血）失调。尽管组织驻留干细胞中的缺陷显然促成了这些表型，但尚不清楚它们在多大程度上反映了干细胞内在的改变，或者是与年龄相关的干细胞支持性微环境或小生境的变化。在这里，我们使用补充的体内和体外异时模型表明，支持干细胞的小生境细胞的与年龄相关的变化通过导致造血干细胞功能障碍而扰乱正常的造血作用。此外，我们发现，小生境细胞中的年龄依赖性缺陷是系统性调节的，可以通过暴露于年轻的循环系统或通过中和骨髓微环境中的保守长寿调节剂胰岛素样生长因子-1 来逆转。总之，这些结果表明局部和全身因素在信号传递与年龄相关的造血衰退方面具有新的和关键作用，并突出了一个新模型，即年老动物血液中的因子通过局部小生境细胞作用，诱导与年龄相关的干细胞功能障碍。
