CELL AUTONOMOUS AND NON-AUTONOMOUS MECHANISMS OF STEM CELL DEFECTS WITH AGING

. 我们证明了从自然衰老的野生型（WT）小鼠和模拟人类早老性综合征的小鼠（ERCCI缺陷小鼠）的骨骼肌中分离的肌源性干/祖细胞（MDSPC）在损伤后的增殖、多谱系分化和组织再生方面存在缺陷。这与成体干细胞隔室中的自主缺陷的概念一致，其随着时间的推移而累积，导致与正常和加速老化相关的组织再生和稳态的丧失。然而，也有证据表明，衰老和疾病会影响干细胞生态位，通过非自主机制影响干细胞功能。此外，有强有力的证据表明，在老年小鼠血清中循环的因子影响干/祖细胞功能。因此，目前尚不清楚衰老相关的成体干细胞功能丧失是否主要由细胞自主和/或非自主机制驱动。因此，该项目的一个目标是通过使用ERCCI的组织和细胞类型特异性失活的小鼠模型来表征MDSPC随着衰老而变得功能障碍的机制。拟议的实验将确定随机的内源性损伤是否直接或间接驱动干细胞功能障碍。我们还证明，从年轻的WT小鼠分离的MDSPC腹腔内给药到ERCCI缺陷小鼠的结果在一个显着的寿命和健康的延长，以及增加组织再生和新血管形成。这是通过旁分泌/内分泌机制发生的，因为在观察到益处的所有组织中均未检测到供体细胞。因此，该项目的第二个目标是描述这种旁分泌/内分泌机制，通过这种机制，年轻的MDSPC在全身递送时促进健康和长寿。最后，我们将确定年轻的功能性干细胞分泌的因子，这些因子对赋予它们有益的作用很重要。这些研究的成功完成将带来关于干细胞对维持健康的贡献的新的机制信息，以及基于干细胞的治疗方法来改善人类衰老。

. We demonstrated that muscle-derived stem/progenitor cells (MDSPCs) isolated from the skeletal muscle of naturally aged wild-type (WT) mice and mice that model a human progeroid syndrome (ERCCI-deficient mice) are defective in proliferation, multi-lineage differentiation and tissue regeneration after injury. This is consistent with the notion that autonomous defects in the adult stem cell compartment, which accrue over time, contribute to the loss of tissue regeneration and homeostasis associated with normal and accelerated aging. However, there is also evidence that aging and disease affects the stem cell niche, impacting stem cell function via non-autonomous mechanisms. In addition, there is strong evidence that factors circulating in the serum of aged mice affect stem/progenitor cell function. Therefore, it remains unclear if aging-related loss of adult stem cell function is primarily driven by cell autonomous and/or non-autonomous mechanisms. Thus one goal of this project is to characterize the mechanism through which MDSPCs become dysfunctional with aging using mouse models of tissue- and cell type-specific inactivation of ERCCI. The proposed experiments will determine if stochastic, endogenous damage directly or indirectly drives stem cell dysfunction. We also demonstrated that intraperitoneal administration of MDSPCs isolated from young WT mice into ERCCI-deficient mice results in a significant lifespan and healthspan extension, as well as increased tissue regeneration and neovascularization. This occurred via a paracrine/endocrine mechanism as donor cells were not detected in all tissues in which benefits were seen. Thus a second goal of this project is to characterize this paracrine/endocrine mechanism by which young MDSPCs promote health and longevity when delivered systemically. Finally we will identify the factors secreted by young, functional stem cells that are important for conferring their beneficial effects. The successful completion ofthe proposed studies should lead to novel mechanistic information about the contribution of stem cells to maintaining healthspan and therapeutic stem cell-based approaches to improve human aging.