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Deciphering the Role of Bone Marrow Niche Signals to Hematopoietic Stem Cell Activity

Review of “CXCR4 expression in the bone marrow microenvironment is required for hematopoietic stem and progenitor cell maintenance and early hematopoietic regeneration after myeloablation” from STEM CELLS by Stuart P. Atkinson

The hematopoietic stem/progenitor cells (HSPCs) that provide for the life‐long production of blood and immune cells in adults reside in a bone marrow niche composed of blood vessels, perivascular mesenchymal stem cells (MSC), immune cells, and nerve fibers. The stromal cell-derived factor 1 (SDF1), also known as C-X-C motif chemokine 12 (CXCL12), that derives from MSCs [1] supports the quiescence and retention of HSPCs within the bone marrow [2-4] by binding to the CXCR4 cognate G‐protein coupled receptor [5, 6]; however, the role of the SDF‐1‐CXCR4 signaling pathway within the bone marrow stroma remains unclear.

In their new STEM CELLS article [7], researchers led by Pratibha Singh and Louis M. Pelus (Indiana University School of Medicine, Indianapolis, IN, USA) now report that bone marrow stromal cells express CXCR4 and that SDF‐1‐CXCR4 signaling in the bone marrow stroma helps to regulate HSPC maintenance, self‐renewal, and hematopoietic reconstitution after myeloablation. Overall, Singh et al. establish an unrecognized new level of extrinsic regulation of HSPC maintenance and response to stress.

The authors of this new study first discovered that wild type HSPCs in chimeric mice possessing CXCR4-null bone marrow stroma, a population that includes both MSCs and endothelial cells, displayed decreased quiescence and self-renewal, hyperproliferation, and reduced engraftment and repopulation capacity under steady-state conditions, thereby highlighting a crucial role for CXCR4 in bone marrow cells. A detailed analysis of the CXCR4-null bone marrow stroma revealed a reduction in the number of MSCs caused by their egress into the bloodstream and, therefore, a decrease in the levels of factors such as SDF‐1 that support normal HSPC function, suggesting that CXCR4 helps to regulate MSC retention and hence HSPC maintenance. 

Interestingly, myeloablative irradiation prompted a more severe reduction in bone marrow stromal cells of CXCR4-null mice when compared to wild type mice, and the transplantation of wild type HSPCs into said animals associated with reduced HSPC homing to the bone marrow and a decrease in early hematopoietic reconstitution. Overall, this suggests that CXCR4 acts to protect the stem cell niche and promote early hematopoietic regeneration and HSPC maintenance after radiation‐induced myelosuppression. 

In a previous STEM CELLS study, the authors reported that the antiapoptotic protein Survivin plays a crucial role in MSC survival after irradiation exposure [8], and now, the team provides evidence that CXCR4 signaling attenuates the loss of bone marrow stromal cells by irradiation in vivo by upregulating the expression of Survivin via the PI3K/Akt signaling pathway. 

In summary, this fascinating new study demonstrates, for the first time, that CXCR4 and SDF-1 interactions within the bone marrow stroma help to maintain HSPCs during homeostasis, promote niche regeneration, and induce recovery of hematopoiesis after transplantation. Therefore, the modulation of CXCR4 signaling in the HSPC niche microenvironment may represent an exciting new means to enhance hematopoietic recovery after stem cell transplantation in patients suffering from hematological complications such as leukemia, lymphoma, and aplastic anemia and metabolic disorders such as diabetes.

For more on how the complex interactions between hematopoietic stem/progenitor cells and niche factors control ongoing hematopoiesis, stay tuned to the Stem Cells Portal!

References

  1. Méndez-Ferrer S, Michurina TV, Ferraro F, et al., Mesenchymal and Haematopoietic Stem Cells form a Unique Bone Marrow Niche. Nature 2010;466:829-834.
  2. Nie Y, Han Y-C, and Zou Y-R, CXCR4 is Required for the Quiescence of Primitive Hematopoietic Cells. Journal of Experimental Medicine 2008;205:777-783.
  3. Sugiyama T, Kohara H, Noda M, et al., Maintenance of the Hematopoietic Stem Cell Pool by CXCL12-CXCR4 Chemokine Signaling in Bone Marrow Stromal Cell Niches. Immunity 2006;25:977-988.
  4. Zhang Y, Dépond M, He L, et al., CXCR4/CXCL12 Axis Counteracts Hematopoietic Stem Cell Exhaustion Through Selective Protection Against Oxidative Stress. Scientific Reports 2016;6:37827.
  5. Ma Q, Jones D, Borghesani PR, et al., Impaired B-Lymphopoiesis, Myelopoiesis, and Derailed Cerebellar Neuron Migration in CXCR4- and SDF-1-deficient Mice. Proceedings of the National Academy of Sciences 1998;95:9448.
  6. Peled A, Grabovsky V, Habler L, et al., The Chemokine SDF-1 Stimulates Integrin-mediated Arrest of CD34+ Cells on Vascular Endothelium Under Shear Flow. The Journal of Clinical Investigation 1999;104:1199-1211.
  7. Singh P, Mohammad KS, and Pelus LM, CXCR4 expression in the bone marrow microenvironment is required for hematopoietic stem and progenitor cell maintenance and early hematopoietic regeneration after myeloablation. STEM CELLS 2020;38:849-859.
  8. Singh P, Fukuda S, Liu L, et al., Survivin Is Required for Mouse and Human Bone Marrow Mesenchymal Stromal Cell Function. STEM CELLS 2018;36:123-129.