Enhancing the Clinical Potential of Umbilical Cord Blood on Hematopoietic Recovery

Review of “Ex Vivo Expansion of CD34+CD90+CD49f+ Hematopoietic Stem and Progenitor Cells from Non-enriched Umbilical Cord Blood with Azole Compounds” from STEM CELLS Translational Medicine by Stuart P. Atkinson

Low hematopoietic stem and progenitor cell (HSPC) counts currently represent a crucial obstacle to the use of umbilical cord blood (UCB) transplantation to promote hematopoietic recovery [1]. Ex vivo methods employed to expand UCB samples require extended coculture periods and/or unwieldy selection steps [2], problems that have prompted the search for minimalistic and more rapid approaches to boost clinical potential. 

Now, a new STEM CELLS Translational Medicine article from the lab of William Hwang Ying Khee (National Cancer Center Singapore) describes the author’s efforts to screen for compounds that can directly expand HSPCs in non-enriched UCB samples. Bari et al. report that a compound similar to the p38α-MAPK inhibitor SB203580 [3, 4] significantly expands HSPC number in UCB samples and enhances primary and secondary engraftment in an immunodeficient mouse model [5].

Initial analyses employed freshly-thawed UCB mononuclear cells cultured in expansion medium (StemSpan-Serum Free Expansion Media or StemSpan-Animal Component Free Media) supplemented with a human cytokine/small molecule cocktail containing stem cell factor (SCF) thrombopoietin (TPO), FLT-3 Ligand (FLT-3L) and insulin-like growth factor binding protein-2 (IGFBP-2). During the screening of a proprietary library of >50 small molecules, the authors discovered that treatment with the “C7” SB203580-analog resulted in a 3-4-fold increase of absolute viable hematopoietic progenitor cells (HPCs = CD45+CD34+CD38-CD45RA-) compared to control cultures. While encouraging, analysis of the rarer primitive HSPC population (CD34+CD90+CD49f+) after treatment with C7 pointed to a greater-than 600-fold increase in number and a significant increase in the generation of functional colonies from treated cells.

Moving in vivo, the transplantation of C7-treated UCB cells into immunodeficient mice led to a significant increase in human blood cells (CD45+) in the peripheral blood and elevated engraftment of common progenitors (CD45+CD34+) in the bone marrow at three weeks when compared to controls. Encouragingly, the grafts permitted long-term bone marrow hematopoiesis with sustained human CD45 cell engraftment in secondary recipients.

While the use of C7 to expand HSPCs from unsorted UCB samples for hematopoietic recovery seems to be a winner, the authors suggest further pre-clinical investigations to reveal the putative mechanism of action of C7 and the further optimization of the expansion and transplantation steps before clinical testing.

For more on the exciting future of C7 and the clinical potential of umbilical cord blood for hematopoietic recovery, stay tuned to the Stem Cells Portal!

References

1. Ballen KK, Gluckman E, and Broxmeyer HE, Umbilical cord blood transplantation: the first 25 years and beyond. Blood 2013;122:491-498.
2. Pineault N and Abu-Khader A, Advances in umbilical cord blood stem cell expansion and clinical translation. Experimental Hematology 2015;43:498-513.
3. Zou J, Zou P, Wang J, et al., Inhibition of p38 MAPK activity promotes ex vivo expansion of human cord blood hematopoietic stem cells. Annals of Hematology 2012;91:813-823.
4. Wang Y, Kellner J, Liu L, et al., Inhibition of p38 Mitogen-Activated Protein Kinase Promotes Ex Vivo Hematopoietic Stem Cell Expansion. Stem Cells and Development 2011;20:1143-1152.
5. Bari S, Zhong Q, Fan X, et al., Ex Vivo Expansion of CD34+CD90+CD49f+ Hematopoietic Stem and Progenitor Cells from Non‐Enriched Umbilical Cord Blood with Azole Compounds. STEM CELLS Translational Medicine 2018;7:376-393.