Hartman Institute for Therapeutic Organ Regeneration

Endothelial jagged-2 sustains hematopoietic stem and progenitor reconstitution after myelosuppression.

TitleEndothelial jagged-2 sustains hematopoietic stem and progenitor reconstitution after myelosuppression.
Publication TypeJournal Article
Year of Publication2017
AuthorsGuo P, Poulos MG, Palikuqi B, Badwe CR, Lis R, Kunar B, Ding B-S, Rabbany SY, Shido K, Butler JM, Rafii S
JournalJ Clin Invest
Volume127
Issue12
Pagination4242-4256
Date Published2017 Dec 01
ISSN1558-8238
KeywordsAdult Stem Cells, Allografts, Animals, Cell Cycle Proteins, Gene Deletion, Graft Survival, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Jagged-2 Protein, Mice, Mice, Transgenic, Receptor, Notch2, Signal Transduction, Transcription Factor HES-1
Abstract

<p>Angiocrine factors, such as Notch ligands, supplied by the specialized endothelial cells (ECs) within the bone marrow and splenic vascular niche play an essential role in modulating the physiology of adult hematopoietic stem and progenitor cells (HSPCs). However, the relative contribution of various Notch ligands, specifically jagged-2, to the homeostasis of HSPCs is unknown. Here, we show that under steady state, jagged-2 is differentially expressed in tissue-specific vascular beds, but its expression is induced in hematopoietic vascular niches after myelosuppressive injury. We used mice with EC-specific deletion of the gene encoding jagged-2 (Jag2) to demonstrate that while EC-derived jagged-2 was dispensable for maintaining the capacity of HSPCs to repopulate under steady-state conditions, by activating Notch2 it did contribute to the recovery of HSPCs in response to myelosuppressive conditions. Engraftment and/or expansion of HSPCs was dependent on the expression of endothelial-derived jagged-2 following myeloablation. Additionally, jagged-2 expressed in bone marrow ECs regulated HSPC cell cycle and quiescence during regeneration. Endothelial-deployed jagged-2 triggered Notch2/Hey1, while tempering Notch2/Hes1 signaling in HSPCs. Collectively, these data demonstrate that EC-derived jagged-2 activates Notch2 signaling in HSPCs to promote hematopoietic recovery and has potential as a therapeutic target to accelerate balanced hematopoietic reconstitution after myelosuppression.</p>

DOI10.1172/JCI92309
Alternate JournalJ Clin Invest
PubMed ID29058691
PubMed Central IDPMC5707154
Grant ListR01 HL133021 / HL / NHLBI NIH HHS / United States
R01 CA204308 / CA / NCI NIH HHS / United States
U01 HL099997 / HL / NHLBI NIH HHS / United States
R01 HL115128 / HL / NHLBI NIH HHS / United States
R01 HL097797 / HL / NHLBI NIH HHS / United States
T32 HD060600 / HD / NICHD NIH HHS / United States
R01 HL119872 / HL / NHLBI NIH HHS / United States
U54 CA163167 / CA / NCI NIH HHS / United States
R01 HL128158 / HL / NHLBI NIH HHS / United States
R01 DK095039 / DK / NIDDK NIH HHS / United States

Weill Cornell Medicine
Hartman Institute for Therapeutic Organ Regeneration
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