Title | Endothelial jagged-2 sustains hematopoietic stem and progenitor reconstitution after myelosuppression. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Guo P, Poulos MG, Palikuqi B, Badwe CR, Lis R, Kunar B, Ding B-S, Rabbany SY, Shido K, Butler JM, Rafii S |
Journal | J Clin Invest |
Volume | 127 |
Issue | 12 |
Pagination | 4242-4256 |
Date Published | 2017 Dec 01 |
ISSN | 1558-8238 |
Keywords | Adult 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> |
DOI | 10.1172/JCI92309 |
Alternate Journal | J Clin Invest |
PubMed ID | 29058691 |
PubMed Central ID | PMC5707154 |
Grant List | R01 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 |