| Abstract
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, selfrenewal,
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. Hypoxiainducible
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. |