ABCG2-Expressing Clonal Repopulating Endothelial Cells Serve to Form and Maintain Blood Vessels

Author:

Lin Yang123ORCID,Gil Chang-Hyun24ORCID,Banno Kimihiko25ORCID,Yokoyama Masataka16,Wingo Matthew7ORCID,Go Ellen28ORCID,Prasain Nutan2,Liu Ying1ORCID,Hato Takashi9ORCID,Naito Hisamichi10ORCID,Wakabayashi Taku101112ORCID,Sominskaia Musia1,Gao Meng1,Chen Kevin1ORCID,Geng Fuqiang1,Gomez Salinero Jesus Maria1ORCID,Chen Sisi2313,Shelley W. Christopher2,Yoshimoto Momoko214ORCID,Li Calzi Sergio1516ORCID,Murphy Michael P.4,Horie Kyoji5ORCID,Grant Maria B.1516ORCID,Schreiner Ryan1ORCID,Redmond David1ORCID,Basile David P.17ORCID,Rafii Shahin1ORCID,Yoder Mervin C.2318ORCID

Affiliation:

1. Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine (Y. Lin, M. Yokoyama, Y. Liu, M.S., M.G., K.C., F.G., J.M.G.S., R.S., D.R., S.R.), Weill Cornell Medicine, New York, NY.

2. Department of Pediatrics, Herman B. Wells Center for Pediatric Research (Y. Lin, C.-H.G., K.B., E.G., N.P., S.C., W.C.S., M. Yoshimoto, M.C.Y.), Indiana University School of Medicine, Indianapolis.

3. Departments of Biochemistry and Molecular Biology (Y. Lin, S.C., M.C.Y.), Indiana University School of Medicine, Indianapolis.

4. Surgery (C.-H.G., M.P.M.), Indiana University School of Medicine, Indianapolis.

5. Department of Physiology II, Nara Medical University, Kashihara, Nara, Japan (K.B., K.H.).

6. Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Japan (M. Yokoyama).

7. Department of Cardiothoracic Surgery (M.W.), Weill Cornell Medicine, New York, NY.

8. Division of Pediatric Rheumatology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA (E.G.).

9. Medicine (T.H.), Indiana University School of Medicine, Indianapolis.

10. Department of Vascular Physiology, Kanazawa University School of Medicine, Japan (H.N., T.W.).

11. Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Japan (T.W.).

12. Mid Atlantic Retina, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA (T.W.).

13. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY (S.C.).

14. Center for Immunobiology, Department of Investigative Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo (M. Yoshimoto).

15. Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute (S.L.C., M.B.G.), Indiana University School of Medicine, Indianapolis.

16. Department of Ophthalmology, University of Alabama at Birmingham (S.L.C., M.B.G.).

17. Anatomy, Cell Biology & Physiology (D.P.B.), Indiana University School of Medicine, Indianapolis.

18. Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, PA (M.C.Y.).

Abstract

BACKGROUND: Most organs are maintained lifelong by resident stem/progenitor cells. During development and regeneration, lineage-specific stem/progenitor cells can contribute to the growth or maintenance of different organs, whereas fully differentiated mature cells have less regenerative potential. However, it is unclear whether vascular endothelial cells (ECs) are also replenished by stem/progenitor cells with EC-repopulating potential residing in blood vessels. It has been reported recently that some EC populations possess higher clonal proliferative potential and vessel-forming capacity compared with mature ECs. Nevertheless, a marker to identify vascular clonal repopulating ECs (CRECs) in murine and human individuals is lacking, and, hence, the mechanism for the proliferative, self-renewal, and vessel-forming potential of CRECs is elusive. METHODS: We analyzed colony-forming, self-renewal, and vessel-forming potential of ABCG2 (ATP binding cassette subfamily G member 2)–expressing ECs in human umbilical vessels. To study the contribution of Abcg2 -expressing ECs to vessel development and regeneration, we developed Abcg2Cre Ert2 ;ROSA TdTomato mice and performed lineage tracing during mouse development and during tissue regeneration after myocardial infarction injury. RNA sequencing and chromatin methylation chromatin immunoprecipitation followed by sequencing were conducted to study the gene regulation in Abcg2 -expressing ECs. RESULTS: In human and mouse vessels, ECs with higher ABCG2 expression (ABCECs) possess higher clonal proliferative potential and in vivo vessel-forming potential compared with mature ECs. These cells could clonally contribute to vessel formation in primary and secondary recipients after transplantation. These features of ABCECs meet the criteria of CRECs. Results from lineage tracing experiments confirm that Abcg2 -expressing CRECs ( Abc CRECs) contribute to arteries, veins, and capillaries in cardiac tissue development and vascular tissue regeneration after myocardial infarction. Transcriptome and epigenetic analyses reveal that a gene expression signature involved in angiogenesis and vessel development is enriched in Abc CRECs. In addition, various angiogenic genes, such as Notch2 and Hey2 , are bivalently modified by trimethylation at the 4th and 27th lysine residue of histone H3 (H3K4me3 and H3K27me3) in Abc CRECs. CONCLUSIONS: These results are the first to establish that a single prospective marker identifies CRECs in mice and human individuals, which holds promise to provide new cell therapies for repair of damaged vessels in patients with endothelial dysfunction.

Publisher

Ovid Technologies (Wolters Kluwer Health)

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