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Induced Homing of Stem Cells Improves Hematopoietic Stem Cell Transplantation Outcomes

Review of “Thrombopoietin enhances hematopoietic stem and progenitor cell homing by impeding MMP-9 expression” from STEM CELLS Translational Medicine by Stuart P. Atkinson 

The efficient homing of hematopoietic stem and progenitor cells (HSPCs) to the bone marrow can significantly influence hematopoietic repopulation in patients undergoing hematopoietic stem cell transplantation (HSCT), as studies have established that the majority of HSPCs can become trapped or “tethered” in various non-hematopoietic organs [1]. Therefore, targeting migration and homing to the bone marrow to enhance transplantation outcomes may represent an exciting alternative to the in vitro-expansion of rare HSPCs present within the umbilical cord blood, for example, required to generate therapeutically relevant numbers of cells [2].

Researchers led by Hengxiang Wang (Medical Center of Air Forces, PLA), Yanhua Li (Beijing Institute of Radiation Medicine), and Xuetao Pei (Institute of Health Service and Transfusion Medicine, Beijing, China) recently evaluated the potentially beneficial effect of thrombopoietin treatment as a means to improve outcomes following HSCT. Previous research established that thrombopoietin, a glycoprotein hormone, regulates hematopoiesis and HSC self‐renewal and quiescence [3] and can also promote hematopoietic recovery and HSPC engraftment in an irradiated mouse model due to increased proliferation and survival [4]. 

In their new STEM CELLS Translational Medicine article [5], Liu et al. discovered that a single dose of thrombopoietin after bone marrow transplantation fostered significant improvements in the homing of HSPCs to the bone marrow and short‐ and long‐term engraftment in model mice. Most encouragingly, these findings prompted a clinical trial of thrombopoietin treatment in patients receiving haploidentical bone marrow and peripheral blood transplantation; encouragingly, a single dose of thrombopoietin improved platelet engraftment outcomes, especially in patients with severe aplastic anemia. 

At the mechanistic level, the authors found evidence that thrombopoietin treatment enhanced HSPC homing by the downregulated expression of matrix metalloproteinase 9 (MMP-9) in bone marrow cells, in agreement with another study that suggested that thrombopoietin affected MMP‐9 in an ischemic brain model [6]. Reduced MMP-9 activity then induced an increase in levels of the stromal cell-derived factor 1α (SDF-1) chemokine within the bone marrow niche, presumably due to the inhibition of SDF-1 degradation [7]. As HSPCs express high levels of the C-X-C chemokine receptor type 4 (CXCR-4) SDF-1 receptor, the authors hypothesize that the decrease in MMP-9 activity induced by thrombopoietin treatment enhances HSPC homing via the CXCR-4/SDF-1 axis. Further evidencing the general importance of this interaction, treatment with a compound that interrupts the interaction of SDF-1 with CXCR-4 blocked the effect of thrombopoietin on HSPC homing.

Overall, these findings suggest that increased HSPC homing by thrombopoietin treatment may represent a feasible and straightforward approach to the improvement of clinical outcomes in patients undergoing bone marrow transplants or HSCT.

For more on how improved homing of stem cells can improve hematopoietic stem cell transplantation and other therapeutic outcomes, stay tuned to the Stem Cells Portal!

 

References

  1. Shimizu T, Bannai M, Kawamura H, et al., Organ specificity of c-kit+ lymphoid precursors in the liver, thymus, and bone marrow. European Journal of Haematology 2000;64:416-425.
  2. Copelan EA, Hematopoietic Stem-Cell Transplantation. New England Journal of Medicine 2006;354:1813-1826.
  3. Rongvaux A, Willinger T, Takizawa H, et al., Human thrombopoietin knockin mice efficiently support human hematopoiesis in vivo. Proceedings of the National Academy of Sciences 2011;108:2378.
  4. Wang C, Zhang B, Wang S, et al., Recombinant human thrombopoietin promotes hematopoietic reconstruction after severe whole body irradiation. Scientific Reports 2015;5:12993.
  5. Liu Y, Ding L, Zhang B, et al., Thrombopoietin enhances hematopoietic stem and progenitor cell homing by impeding matrix metalloproteinase 9 expression. STEM CELLS Translational Medicine 2020;9:661-673.
  6. Zhou J, Li J, Rosenbaum DM, et al., Thrombopoietin Protects the Brain and Improves Sensorimotor Functions: Reduction of Stroke-Induced MMP-9 Upregulation and Blood—Brain Barrier Injury. Journal of Cerebral Blood Flow & Metabolism 2010;31:924-933.
  7. Jin F, Zhai Q, Qiu L, et al., Degradation of BM SDF-1 by MMP-9: the role in G-CSF-induced hematopoietic stem/progenitor cell mobilization. Bone Marrow Transplantation 2008;42:581-588.