The nesting mechanisms and programming for the fate of implanted stem cells in the damaged tissue have been critical issues in designing and achieving cell therapies. The fracture site can induce senescence or apoptosis based on the surrounding harsh conditions, hypoxia, and oxidative stress (OS). Respiration deficiency, disruption in energy metabolism, and consequently OS induction change the biophysical, biochemical, and cellular components of the native tissue. Additionally, the homeostatic molecular players and cell signaling might be changed. Despite all aforementioned issues, in the native stem cell niche, physiological hypoxia is not toxic; rather, it is vitally required for homing, self-renewal, and differentiation. Hence, the key macromolecular players involved in the support of stem cell survival and re-adaptation to a new dysfunctional niche must be understood for managing the cell therapy outcome. Hypoxia-inducible factor 1-alpha is the master transcriptional regulator, involved in the cell response to hypoxia and the adaptation of stem cells to a new niche. This protein is regulated by interaction with sirtuins. Sirtuins are highly conserved NAD+-dependent enzymes that monitor the cellular energy status and modulate gene transcription, genome stability, and energy metabolism in response to environmental signals to modulate the homing and fate of stem cells. Herein, new insights into the nesting of stem cells in hypoxic–ischemic injured tissues were provided and their programming in a new dysfunctional niche along with the involved complex macromolecular players were critically discussed.

中文翻译：

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移植干细胞在缺氧/缺血损伤组织中的嵌套和命运：HIF1α/sirtuins 和下游分子相互作用的作用

受损组织中植入干细胞命运的嵌套机制和编程一直是设计和实现细胞疗法的关键问题。骨折部位可根据周围的恶劣条件、缺氧和氧化应激 (OS) 诱导衰老或细胞凋亡。呼吸不足、能量代谢中断以及随后的 OS 诱导会改变天然组织的生物物理、生物化学和细胞成分。此外，稳态分子参与者和细胞信号可能会发生变化。尽管存在上述所有问题，但在天然干细胞生态位中，生理性缺氧是无毒的；相反，它是归巢、自我更新和分化所必需的。因此，必须了解参与支持干细胞存活和重新适应新的功能失调生态位的关键大分子参与者，以管理细胞治疗结果。缺氧诱导因子 1-alpha 是主要的转录调节因子，参与细胞对缺氧的反应和干细胞对新环境的适应。这种蛋白质通过与 sirtuins 的相互作用来调节。Sirtuins 是高度保守的 NAD+ 依赖性酶，可监测细胞能量状态并调节基因转录、基因组稳定性和能量代谢以响应环境信号以调节干细胞的归巢和命运。在此处，