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Osteoblast-secreted Factors Enhance Platelet Engraftment of Umbilical Cord Blood Progenitors

Review of “Paracrine Factors Released by Osteoblasts Provide Strong Platelet Engraftment Properties” from STEM CELLS by Stuart P. Atkinson 

Previous studies from the laboratory of Nicolas Pineault (Canadian Blood Services, Ottawa, Ontario, Canada) discovered that the coculture of umbilical cord blood progenitor cells with mesenchymal stem cell (MSC)-derived osteoblasts promoted cell expansion [1]. Additionally, the team established that conditioned medium derived from immature MSC‐derived osteoblasts (OCM) supported umbilical cord blood progenitor expansion to a greater extent than conditioned medium obtained from MSCs or mature osteoblasts [2, 3]. However, OCM treatment also improved the engraftment properties of expanded umbilical cord blood progenitors leading to improved reconstitution of human platelets in humanized mice [3],  thereby suggesting OCM treatment as a potentially exciting means to boost the slow platelet engraftment kinetics generally associated with umbilical cord blood transplantation [4].

Given these findings, Abu‐Khader et al. set out to delineate the crucial factors involved in the improvement of platelet engraftment activity of expanded umbilical cord blood progenitors by OCM, and their new STEM CELLS study now establishes the overarching importance of insulin‐like growth factor signaling and the subsequent activation of transcriptional activation complexes [5].

Osteoblasts normally regulate hematopoiesis in vivo through various mechanisms, including the release of paracrine factors. In the present study, initial limiting dilution transplantation assays demonstrated that soluble prosurvival and mitogenic factor-containing OCM synergized with exogenously added cytokines to enhance the generation of umbilical cord blood progenitors that displayed both short- and long-term platelet engraftment properties. Furthermore, OCM treatment induced the expression of a range of cell-surface receptors involved in hematopoietic stem/progenitor cell trafficking to the bone marrow by umbilical cord blood progenitors, suggesting an increase in engraftment abilities. 

Looking for the specific factors in OCM that may promote the proliferation and enhanced engraftment of umbilical cord blood progenitors, the authors highlighted the overexpression of insulin‐like growth factor (IGF)‐2 in OCM when compared to control MSC conditioned medium. Indeed, further assessments suggested that IGF2 interaction with IGF1R in umbilical cord blood progenitors and subsequent activation of the β‐catenin/TCF transcriptional activation complex plays a significant role on the growth‐promoting activity of OCM on umbilical cord blood progenitors. However, the factors responsible for the modulation of homing‐related receptors remain to be determined.

While providing for a deeper understanding of the paracrine regulatory activities of osteoblasts on progenitor cells of the hematopoietic system, the identification of regulatory mechanisms such as the IGF2-IGF1R-β‐catenin axis may also lead to the development of strategies to improve the platelet engraftment activity of ex vivo expanded stem and progenitor cells for transplantation purposes.

For more on new approaches to improve the applicability of umbilical cord blood stem and progenitor cells, stay tuned to the Stem Cells Portal!

Results

  1. Çelebi B, Mantovani D, and Pineault N, Irradiated mesenchymal stem cells improve the ex vivo expansion of hematopoietic progenitors by partly mimicking the bone marrow endosteal environment. Journal of Immunological Methods 2011;370:93-103.
  2. Alsheikh M, Abu-Khader A, Michalicka M, et al., Impact of osteoblast maturation on their paracrine growth enhancing activity on cord blood progenitors. European Journal of Haematology 2017;98:542-552.
  3. Dumont N, Boyer L, Émond H, et al., Medium conditioned with mesenchymal stromal cell–derived osteoblasts improves the expansion and engraftment properties of cord blood progenitors. Experimental Hematology 2014;42:741-752.e1.
  4. Cheung AMS, Leung D, Rostamirad S, et al., Distinct but phenotypically heterogeneous human cell populations produce rapid recovery of platelets and neutrophils after transplantation. Blood 2012;119:3431-3439.
  5. Abu-Khader A, Law KW, Jahan S, et al., Paracrine Factors Released by Osteoblasts Provide Strong Platelet Engraftment Properties. Stem Cells 2019;37:345-356.