The Journal of Experimental Medicine
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Published online 27 December 2005 doi:10.1084/jem.20051714
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 1, 73-85
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ARTICLE

 Purified hematopoietic stem cell engraftment of rare niches corrects severe lymphoid deficiencies without host conditioning

Deepta Bhattacharya, Derrick J. Rossi, David Bryder, and Irving L. Weissman

Department of Pathology, Institute of Cancer and Stem Cell Biology and Medicine, Stanford University School of Medicine, Stanford, CA 94305

CORRESPONDENCE: Deepta Bhattacharya: deepta{at}stanford.edu

In the absence of irradiation or other cytoreductive conditioning, endogenous hematopoietic stem cells (HSCs) are thought to fill the unique niches within the bone marrow that allow maintenance of full hematopoietic potential and thus prevent productive engraftment of transplanted donor HSCs. By transplantation of purified exogenous HSCs into unconditioned congenic histocompatible strains of mice, we show that ~0.1–1.0% of these HSC niches are available for engraftment at any given point and find no evidence that endogenous HSCs can be displaced from the niches they occupy. We demonstrate that productive engraftment of HSCs within these empty niches is inhibited by host CD4+ T cells that recognize very subtle minor histocompatibility differences. Strikingly, transplantation of purified HSCs into a panel of severe combined immunodeficient (SCID) mice leads to a rapid and complete rescue of lymphoid deficiencies through engraftment of these very rare niches and expansion of donor lymphoid progenitors. We further demonstrate that transient antibody-mediated depletion of CD4+ T cells allows short-term HSC engraftment and regeneration of B cells in a mouse model of B(-) non-SCID. These experiments provide a general mechanism by which transplanted HSCs can correct hematopoietic deficiencies without any host conditioning or with only highly specific and transient lymphoablation.

Abbreviations used: APC, allophycocyanin; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; GMP, granulocyte macrophage progenitor; GVHD, graft-versus-host disease; HSC, hematopoietic stem cell; LT, long-term; MEP, megakaryocyte erythrocyte progenitor; NP, 4-hydroxy-3-nitrophenylacetyl.


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