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How the Aged Stem Cell Niche Impacts Rejuvenated HSCs

Review of “An aged bone marrow niche restrains rejuvenated hematopoietic stem cells” from STEM CELLS by Stuart P. Atkinson

The transplantation of young hematopoietic stem cells (HSCs) into an aged bone marrow niche induces hallmarks indicative of stem cell aging [1, 2], thereby implying a crucial role of the stem cell niche in the aging process. In a previous mouse model study, researchers led by Hartmut Geiger (Ulm University, Germany) demonstrated that the secretion of the cytokine Osteopontin by the aged niche induced signs of aging in transplanted young HSCs [2] in a mechanism that involved modulating the activity of the small Rho GTPase cell division control protein 42 (Cdc42) cell cycle regulator and altering cell polarity [2, 3].

Importantly, treatment of aged HSCs with a Cdc42 inhibitor [4] prompts long-term sustained rejuvenation [5-7]; therefore, the team’s recent research, whose findings have been published in a recent STEM CELLS article [8], sought to determine the impact of the aged niche on rejuvenated aged HSCs. Overall, their recent research now suggests that the rejuvenation of the hematopoietic system must take HSCs and the stem cell niche into account.

In their exciting new study, Guidi et al. discovered that the aged stem cell niche effectively restrained the function of aged HSCs rejuvenated ex vivo through treatment with the Cdc42 inhibitor; furthermore, they confirmed a critical role for a mechanism involving the low-level expression of Osteopontin from the aged niche. Therefore, these findings strongly suggest that the in vivo rejuvenation of the hematopoietic system in situations such as aging‐associated leukemia or aging‐associated immune remodeling will require the rejuvenation of both HSCs and the stem cell niche.

In summary, these data suggest that rejuvenated aged HSCs appropriately function when transplanted into young recipients due to stem cell-intrinsic and stem cell-extrinsic contributions; however, the stem cell niche of aged recipients has the capacity to revert the youthful phenotype of rejuvenated aged HSCs after transplantation, due, in part, to Osteopontin expression. Can we now target Osteopontin to boost the rejuvenation of the aged hematopoietic system?

For more on stem cell rejuvenation and the critical role of the stem cell niche, stay tuned to the Stem Cells Portal!

References

  1. Ergen AV, Boles NC, and Goodell MA, Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing. Blood 2012;119:2500-2509.
  2. Guidi N, Sacma M, Ständker L, et al., Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells. The EMBO Journal 2017;36:840-853.
  3. Grassinger J, Haylock DN, Storan MJ, et al., Thrombin-cleaved osteopontin regulates hemopoietic stem and progenitor cell functions through interactions with α9β1 and α4β1 integrins. Blood 2009;114:49-59.
  4. Liu W, Du W, Shang X, et al., Rational identification of a Cdc42 inhibitor presents a new regimen for long-term hematopoietic stem cell mobilization. Leukemia 2019;33:749-761.
  5. Leins H, Mulaw M, Eiwen K, et al., Aged murine hematopoietic stem cells drive aging-associated immune remodeling. Blood 2018;132:565-576.
  6. Florian MC, Klose M, Sacma M, et al., Aging alters the epigenetic asymmetry of HSC division. PLOS Biology 2018;16:e2003389.
  7. Florian Maria C, Dörr K, Niebel A, et al., Cdc42 Activity Regulates Hematopoietic Stem Cell Aging and Rejuvenation. Cell Stem Cell 2012;10:520-530.
  8. Guidi N, Marka G, Sakk V, et al., An aged bone marrow niche restrains rejuvenated hematopoietic stem cells. STEM CELLS 2021;39:1101-1106.