한빛사논문
- 조회488
Yang Lin, PhD*; Chang-Hyun Gil, PhD*; Kimihiko Banno, MD*; Masataka Yokoyama, MD; Matthew Wingo, MD; Ellen Go, MD; Nutan Prasain, PhD; Ying Liu, PhD; Takashi Hato, MD; Hisamichi Naito, MD, PhD; Taku Wakabayashi, MD; Musia Sominskaia, BS; Meng Gao, MS; Kevin Chen, BS; Fuqiang Geng, MD; Jesus Maria Gomez Salinero, PhD; Sisi Chen, PhD; W. Christopher Shelley, BA; Momoko Yoshimoto, MD, PhD; Sergio Li Calzi, PhD; Michael P. Murphy, MD; Kyoji Horie, MD; Maria B. Grant, MD; Ryan Schreiner, PhD; David Redmond, PhD; David P. Basile, PhD; Shahin Rafii, MD; Mervin C. Yoder, MD
Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Re-generation, Ansary Stem Cell Institute, Department of Medicine (Y. Lin, M. Yo-koyama, Y. Liu, M.S., M.G., K.C., F.G., J.M.G.S., R.S., D.R., S.R.), and Department of Cardiothoracic Surgery (M.W.), Weill Cornell Medicine, New York, NY. 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.), Departments of Biochemistry and Molecular Biology (Y. Lin, S.C., M.C.Y.), Surgery (C.-H.G., M.P.M.), Medicine (T.H.), and Anatomy, Cell Biology & Physiology (D.P.B.), and Department of Ophthalmol-ogy, Eugene and Marilyn Glick Eye Institute (S.L.C., M.B.G.), Indiana University School of Medicine, Indianapolis. Department of Physiology II, Nara Medical Uni-versity, Kashihara, Nara, Japan (K.B., K.H.). Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Japan (M. Yokoyama). Depart-ment of Pediatrics, Division of Pediatric Rheumatology, Riley Hospital for Children, Indianapolis, IN (E.G.). Department of Vascular Physiology, Kanazawa University School of Medicine, Japan (H.N., T.W.). Department of Ophthalmology, Osaka Uni-versity Graduate School of Medicine, Suita, Japan (T.W.). Mid Atlantic Retina, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA (T.W.). Human Oncol-ogy and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY (S.C.). Center for Immunobiology, Department of Investigative Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo (M. Yoshimoto). Department of Ophthalmology, University of Alabama at Birming-ham (S.L.C., M.B.G.). Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, PA (M.C.Y.)
*Y. Lin, C.-H. Gil, and K. Banno contributed equally.
Correspondence to: Mervin C. Yoder, MD, r Shahin Rafii, MD, or Yang Lin, PhD,
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 Abcg2CreErt2;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 (AbcCRECs) 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 AbcCRECs. 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 AbcCRECs.
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.
논문정보
- Research article
- 2024년 04월 (BRIC 등록일 2024-05-02)
- 국외 연구진
- 의약학 > 재생의학
댓글 작성 로그인
팝업 닫기관련 링크
연구자 키워드
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기
