NDLI: Cell-intrinsic in vivo requirement for the E47-p21 pathway in long-term hematopoietic stem cells.

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Cell-intrinsic in vivo requirement for the E47-p21 pathway in long-term hematopoietic stem cells.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Borghesi, Lisa Santos, Patricia M. Ding, Ying
Description	Author Affiliation: Santos PM ( Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.)
Abstract	Major regulators of long-term hematopoietic stem cell (LT-HSC) self-renewal and proliferation have been identified, but knowledge of their in vivo interaction in a linear pathway is lacking. In this study, we show a direct genetic link between the transcription factor E47 and the major cell cycle regulator p21 in controlling LT-HSC integrity in vivo under repopulation stress. Numerous studies have shown that E47 activates p21 transcription in hematopoietic subsets in vitro, and we now reveal the in vivo relevance of the E47-p21 pathway by reducing the gene dose of each factor individually (E47(het) or p21(het)) versus in tandem (E47(het)p21(het)). E47(het)p21(het) LT-HSCs and downstream short-term hematopoietic stem cells exhibit hyperproliferation and preferential susceptibility to mitotoxin compared to wild-type or single haploinsufficient controls. In serial adoptive transfers that rigorously challenge self-renewal, E47(het)p21(het) LT-HSCs dramatically and progressively decline, indicating the importance of cell-intrinsic E47-p21 in preserving LT-HSCs under stress. Transient numeric recovery of downstream short-term hematopoietic stem cells enabled the production of functionally competent myeloid but not lymphoid cells, as common lymphoid progenitors were decreased, and peripheral lymphocytes were virtually ablated. Thus, we demonstrate a developmental compartment-specific and lineage-specific requirement for the E47-p21 pathway in maintaining LT-HSCs, B cells, and T cells under hematopoietic repopulation stress in vivo.
ISSN	00221767
e-ISSN	15506606
DOI	10.4049/jimmunol.1302502
Journal	The Journal of Immunology
Issue Number	1
Volume Number	192
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2014-01-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Cyclin-dependent Kinase Inhibitor P21 Metabolism Hematopoietic Stem Cells Signal Transduction Transcription Factor 3 Animals Cell Differentiation Genetics Fluorouracil Toxicity Gene Expression Regulation Haploinsufficiency Hematopoiesis Drug Effects Cytology Homeostasis Mice Mice, Knockout Myeloid Cells Protein Binding Stress, Physiological Research Support, N.i.h., Extramural Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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