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 Blood, 15 April 2007, Vol. 109, No. 8, pp. 3579-3587.
Prepublished online as a Blood First Edition Paper on January 9, 2007; DOI 10.1182/blood-2006-08-039842.

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TRANSPLANTATION

Enhanced T-cell reconstitution by hematopoietic progenitors expanded ex vivo using the Notch ligand Delta1

Mari H. Dallas1,2, Barbara Varnum-Finney1, Paul J. Martin1, and Irwin D. Bernstein1,2

1 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; 2 Department of Pediatrics, University of Washington, Seattle

A physiologic role for Notch signaling in hematopoiesis has been clearly defined in lymphoid differentiation, with evidence suggesting a critical role in T-cell versus B-cell fate decisions. Previously, we demonstrated that activation of endogenous Notch receptors by culture of murine lin–Sca-1+c-kit+ (LSK) hematopoietic progenitors with exogenously presented Notch ligand, Delta1ext-IgG, consisting of the extracellular domain of Delta1 fused to the Fc domain of human IgG1, promoted early T-cell differentiation and increased the number of progenitors capable of short-term lymphoid and myeloid reconstitution. Here we show that culture of LSK precursors with Delta1ext-IgG increases the number of progenitors that are able to rapidly repopulate the thymus and accelerate early T-cell reconstitution with a diversified T-cell receptor repertoire. Most of the early T-cell reconstitution originated from cells that expressed lymphoid-associated antigens: B220, Thy1, CD25, and/or IL7R{alpha}, whereas the most efficient thymic repopulation on a per cell basis originated from the smaller number of cultured cells that did not express lymphoid-associated antigens. These findings demonstrate the potential of Delta1ext-IgG-cultured cells for accelerating early immune reconstitution after hematopoietic cell transplantation.


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B. Varnum-Finney, M. H. Dallas, K. Kato, and I. D. Bernstein
Notch target Hes5 ensures appropriate Notch induced T- versus B-cell choices in the thymus
Blood, March 1, 2008; 111(5): 2615 - 2620.
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