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Enhanced generation of cord blood hematopoietic stem and progenitor cells by culture with StemRegenin1 and Delta1Ext-IgG

Leukemia volume 28, pages 2097–2101 (2014)Cite this article

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Neutropenia after myeloablative conditioning regimens in cord blood transplant (CBT) recipients or following intensive chemotherapy for leukemia is associated with a high mortality risk from infectious complications necessitating interventions to reduce this neutropenic period.1, 2 Several ex vivo expansion approaches have been identified that are capable of generating short-term hematopoietic repopulating cells derived from cord blood (CB) hematopoietic stem/progenitor cells (HSPC) that provide a myeloid bridge until hematopoietic reconstitution occurs.3, 4, 5, 6, 7, 8, 9 However, these have relied on real-time expansion of partially human leukocyte antigen (HLA)-matched units with costs of the unit and manufacturing prohibitive for widespread use. Generating greater number of HSPC per starting cell than is currently achieved will be required to develop a cryopreserved product able to overcome HLA-matching barriers, thereby making it readily and widely available.

Similar to models of leukemic cell self-renewal, we have undertaken a rational approach to maximize proliferation and inhibit differentiation to enhance generation of HSPC. We previously demonstrated that culture of CD34+ CB HSPC in the presence of Delta1Ext-IgG and growth factors results in a 16-fold increase in severe combined immunodeficiency (SCID)-repopulating cells (SRCs).5 Likewise, Boitano et al.3 described an aryl hydrocarbon receptor (AhR) antagonist, StemRegenin1 (SR1), that results in a 17-fold increase in SRC. Here we demonstrate that SR1 combined with Delta1Ext-IgG generates a further threefold improvement in rapid repopulating cells (RRCs) over either agent alone. This is mediated, at least in part, by the Notch target gene, HES1, consistent with the hypothesis that Delta1Ext-IgG is delaying differentiation in the presence of strong cytokine-driven proliferative signals in SR1 cultures.

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Acknowledgements

This work was supported by National Heart, Lung and Blood Institute grant U01HL100395 and National Institutes of Health Ruth L. Kirschstein National Research Service Award T32CA009351 (AD) and K12CA076930 (AD). CD is a Damon Runyon Clinical Investigator. Anthony Boitano and Michael Cooke (Genomics Institute of the Novartis Research Foundation, La Jolla, CA, USA) provided SR1.

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Authors and Affiliations

  1. Clinical Research Division, Pediatric Oncology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    A Dahlberg, C Brashem-Stein, C Delaney & I D Bernstein

  2. Department of Pediatrics, University of Washington, Seattle, WA, USA

    A Dahlberg, C Delaney & I D Bernstein

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  1. A Dahlberg
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  2. C Brashem-Stein
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  3. C Delaney
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Correspondence to I D Bernstein.

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Competing interests

The Fred Hutchinson Cancer Research Center holds a patent on ‘methods for immortalizing cells’ that covers the use of Notch ligand for expansion of hematopoietic stem cells. IDB is an inventor on this patent. The remaining authors declare no conflict of interest.

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Dahlberg, A., Brashem-Stein, C., Delaney, C. et al. Enhanced generation of cord blood hematopoietic stem and progenitor cells by culture with StemRegenin1 and Delta1Ext-IgG. Leukemia 28, 2097–2101 (2014). https://doi.org/10.1038/leu.2014.181

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