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Early production of human neutrophils and platelets post-transplant is severely compromised by growth factor exposure

Posted April 25, 2016 | Publications

Miller PH, Knapp DJ, Beer PA, MacAldaz M, Rabu G, Cheung AM, Wei L, Eaves CJ. Exp Hematol 2016 [Epub ahead of print]

Abstract
The critical human cells that produce neutrophils and platelets within 3 weeks in recipients of hematopoietic transplants are thought to produce these mature blood cells with the same kinetics in sublethally irradiated immunodeficient mice. Quantification of their numbers indicates their relative underrepresentation in cord blood (CB) likely explaining the clinical inadequacy of single CB units to rescue hematopoiesis in myelosuppressed adult patients. We now show that exposure of CD34+ CB cells ex vivo to growth factors (GFs) that markedly expand their numbers and colony-forming cell content, also rapidly (within 24 hours) produces a significant and sustained net loss of their original short-term repopulating activity. This loss of short-term in vivo repopulating activity affects early platelet production faster than early neutrophil output, consistent with their origin from distinct input populations. Moreover, this GF-mediated loss is not abrogated by published strategies to increase progenitor homing despite evidence that the effect on rapid neutrophil production is paralleled in time and amount by a loss of the homing of their committed clonogenic precursors to the bone marrow. These results highlight the inability of in vitro or phenotype assessments to reliably predict clinical engraftment kinetics of cultured CB cells.

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