Apelin Endothelial Niche Cells Control Hematopoiesis and Mediate Vascular Regeneration After Myeloablative Injury

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2019 Nov 26

PMID 31761723

Citations 66

Authors

Qi Chen

Yang Liu

Hyun-Woo Jeong

Martin Stehling

Van Vuong Dinh

Bin Zhou

Ralf H Adams

Affiliations

Soon will be listed here.

Abstract

Radiotherapy and chemotherapy disrupt bone vasculature, but the underlying causes and mechanisms enabling vessel regeneration after bone marrow (BM) transplantation remain poorly understood. Here, we show that loss of hematopoietic cells per se, in response to irradiation and other treatments, triggers vessel dilation, permeability, and endothelial cell (EC) proliferation. We further identify a small subpopulation of Apelin-expressing (Apln) ECs, representing 0.003% of BM cells, that is critical for physiological homeostasis and transplant-induced BM regeneration. Genetic ablation of Apln ECs or Apln-CreER-mediated deletion of Kitl and Vegfr2 disrupt hematopoietic stem cell (HSC) maintenance and contributions to regeneration. Consistently, the fraction of Apln ECs increases substantially after irradiation and promotes normalization of the bone vasculature in response to VEGF-A, which is provided by transplanted hematopoietic stem and progenitor cells (HSPCs). Together, these findings reveal critical functional roles for HSPCs in maintaining vascular integrity and for Apln ECs in hematopoiesis, suggesting potential targets for improving BM transplantation.

Citing Articles

Bone Marrow Endothelial Progenitor Cells remodelling facilitates normal hematopoiesis during Acute Myeloid Leukemia Complete Remission.

Xing T, Hu L, Zhao H, Li C, Wang Z, Shen M Nat Commun. 2024; 15(1):10832.

PMID: 39737962 PMC: 11686104. DOI: 10.1038/s41467-024-55051-x.

Adult skull bone marrow is an expanding and resilient haematopoietic reservoir.

Koh B, Mohanakrishnan V, Jeong H, Park H, Kruse K, Choi Y Nature. 2024; 636(8041):172-181.

PMID: 39537918 PMC: 11618084. DOI: 10.1038/s41586-024-08163-9.

Endothelial heterogeneity in bone marrow: insights across development, adult life and leukemia.

Boueya I, Sandhow L, Albuquerque J, Znaidi R, Passaro D Leukemia. 2024; 39(1):8-24.

PMID: 39528790 PMC: 11717709. DOI: 10.1038/s41375-024-02453-x.

Polyclonal regeneration of mouse bone marrow endothelial cells after irradiative conditioning.

Skulimowska I, Morys J, Sosniak J, Gonka M, Gulati G, Sinha R Cell Rep. 2024; 43(11):114779.

PMID: 39489938 PMC: 11602546. DOI: 10.1016/j.celrep.2024.114779.

The evolving hematopoietic niche during development.

Sanchez-Lanzas R, Jimenez-Pompa A, Ganuza M Front Mol Biosci. 2024; 11:1488199.

PMID: 39417006 PMC: 11480086. DOI: 10.3389/fmolb.2024.1488199.

References

Gerber H, Malik A, Solar G, Sherman D, Liang X, Meng G . VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature. 2002; 417(6892):954-8. DOI: 10.1038/nature00821. View

Pitulescu M, Schmidt I, Giaimo B, Antoine T, Berkenfeld F, Ferrante F . Dll4 and Notch signalling couples sprouting angiogenesis and artery formation. Nat Cell Biol. 2017; 19(8):915-927. DOI: 10.1038/ncb3555. View

Ishikawa E, Gonzalez-Nieto D, Ghiaur G, Dunn S, Ficker A, Murali B . Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells. Proc Natl Acad Sci U S A. 2012; 109(23):9071-6. PMC: 3384185. DOI: 10.1073/pnas.1120358109. View

Kusumbe A, Ramasamy S, Adams R . Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature. 2014; 507(7492):323-328. PMC: 4943525. DOI: 10.1038/nature13145. View

Zhou B, Ding L, Morrison S . Hematopoietic stem and progenitor cells regulate the regeneration of their niche by secreting Angiopoietin-1. Elife. 2015; 4:e05521. PMC: 4411515. DOI: 10.7554/eLife.05521. View

Doan P, Russell J, Himburg H, Helms K, Harris J, Lucas J . Tie2(+) bone marrow endothelial cells regulate hematopoietic stem cell regeneration following radiation injury. Stem Cells. 2012; 31(2):327-37. PMC: 3580267. DOI: 10.1002/stem.1275. View

Gerber H, Hillan K, Ryan A, Kowalski J, Keller G, RANGELL L . VEGF is required for growth and survival in neonatal mice. Development. 1999; 126(6):1149-59. DOI: 10.1242/dev.126.6.1149. View

Haigh J, Morelli P, Gerhardt H, Haigh K, Tsien J, Damert A . Cortical and retinal defects caused by dosage-dependent reductions in VEGF-A paracrine signaling. Dev Biol. 2003; 262(2):225-41. DOI: 10.1016/s0012-1606(03)00356-7. View

Ferrara J, Levine J, Reddy P, Holler E . Graft-versus-host disease. Lancet. 2009; 373(9674):1550-61. PMC: 2735047. DOI: 10.1016/S0140-6736(09)60237-3. View

10.

Himburg H, Termini C, Schlussel L, Kan J, Li M, Zhao L . Distinct Bone Marrow Sources of Pleiotrophin Control Hematopoietic Stem Cell Maintenance and Regeneration. Cell Stem Cell. 2018; 23(3):370-381.e5. PMC: 6482945. DOI: 10.1016/j.stem.2018.07.003. View

11.

Thomas E, Storb R, Clift R, Fefer A, Johnson F, Neiman P . Bone-marrow transplantation (first of two parts). N Engl J Med. 1975; 292(16):832-43. DOI: 10.1056/NEJM197504172921605. View

12.

Ramasamy S, Kusumbe A, Itkin T, Gur-Cohen S, Lapidot T, Adams R . Regulation of Hematopoiesis and Osteogenesis by Blood Vessel-Derived Signals. Annu Rev Cell Dev Biol. 2016; 32:649-675. DOI: 10.1146/annurev-cellbio-111315-124936. View

13.

Jin Y, Wi H, Choi M, Hong S, Bae Y . Regulation of anti-inflammatory cytokines IL-10 and TGF-β in mouse dendritic cells through treatment with Clonorchis sinensis crude antigen. Exp Mol Med. 2014; 46:e74. PMC: 3909892. DOI: 10.1038/emm.2013.144. View

14.

Li X, Hu Z, Jorgenson M, Wingard J, Slayton W . Bone marrow sinusoidal endothelial cells undergo nonapoptotic cell death and are replaced by proliferating sinusoidal cells in situ to maintain the vascular niche following lethal irradiation. Exp Hematol. 2008; 36(9):1143-1156. DOI: 10.1016/j.exphem.2008.06.009. View

15.

Copelan E . Hematopoietic stem-cell transplantation. N Engl J Med. 2006; 354(17):1813-26. DOI: 10.1056/NEJMra052638. View

16.

Jeong H, Hernandez-Rodriguez B, Kim J, Kim K, Enriquez-Gasca R, Yoon J . Transcriptional regulation of endothelial cell behavior during sprouting angiogenesis. Nat Commun. 2017; 8(1):726. PMC: 5620061. DOI: 10.1038/s41467-017-00738-7. View

17.

de Boer J, Williams A, Skavdis G, Harker N, Coles M, Tolaini M . Transgenic mice with hematopoietic and lymphoid specific expression of Cre. Eur J Immunol. 2003; 33(2):314-25. DOI: 10.1002/immu.200310005. View

18.

Helker C, Schuermann A, Pollmann C, Chng S, Kiefer F, Reversade B . The hormonal peptide Elabela guides angioblasts to the midline during vasculogenesis. Elife. 2015; 4. PMC: 4468421. DOI: 10.7554/eLife.06726. View

19.

Tikhonova A, Dolgalev I, Hu H, Sivaraj K, Hoxha E, Cuesta-Dominguez A . The bone marrow microenvironment at single-cell resolution. Nature. 2019; 569(7755):222-228. PMC: 6607432. DOI: 10.1038/s41586-019-1104-8. View

20.

Del Toro R, Prahst C, Mathivet T, Siegfried G, Kaminker J, Larrivee B . Identification and functional analysis of endothelial tip cell-enriched genes. Blood. 2010; 116(19):4025-33. PMC: 4314527. DOI: 10.1182/blood-2010-02-270819. View