학술논문
ABCG2-Expressing Clonal Repopulating Endothelial Cells Serve to Form and Maintain Blood Vessels.
Document Type
Academic Journal
Author
Lin Y; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY. (Y. Lin, M. Yokoyama, Y. Liu, M.S., M.G., K.C., F.G., J.M.G.S., R.S., D.R., S.R.).; 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.).; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis. (Y. Lin, S.C., M.C.Y.).; Gil CH; 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.).; Department of Surgery, Indiana University School of Medicine, Indianapolis. (C.-H.G., M.P.M.).; Banno K; 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.).; Department of Physiology II, Nara Medical University, Kashihara, Nara, Japan (K.B., K.H.).; Yokoyama M; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY. (Y. Lin, M. Yokoyama, Y. Liu, M.S., M.G., K.C., F.G., J.M.G.S., R.S., D.R., S.R.).; Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Japan (M. Yokoyama).; Wingo M; Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY. (M.W.).; Go E; 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.).; Department of Pediatrics, Division of Pediatric Rheumatology, Riley Hospital for Children, Indianapolis, IN (E.G.).; Prasain N; 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.).; Liu Y; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY. (Y. Lin, M. Yokoyama, Y. Liu, M.S., M.G., K.C., F.G., J.M.G.S., R.S., D.R., S.R.).; Hato T; Department of Medicine, Indiana University School of Medicine, Indianapolis. (T.H.).; Naito H; Department of Vascular Physiology, Kanazawa University School of Medicine, Japan (H.N., T.W.).; Wakabayashi T; Department of Vascular Physiology, Kanazawa University School of Medicine, Japan (H.N., T.W.).; Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Japan (T.W.).; Mid Atlantic Retina, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA (T.W.).; Sominskaia M; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY. (Y. Lin, M. Yokoyama, Y. Liu, M.S., M.G., K.C., F.G., J.M.G.S., R.S., D.R., S.R.).; Gao M; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY. (Y. Lin, M. Yokoyama, Y. Liu, M.S., M.G., K.C., F.G., J.M.G.S., R.S., D.R., S.R.).; Chen K; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY. (Y. Lin, M. Yokoyama, Y. Liu, M.S., M.G., K.C., F.G., J.M.G.S., R.S., D.R., S.R.).; Geng F; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY. (Y. Lin, M. Yokoyama, Y. Liu, M.S., M.G., K.C., F.G., J.M.G.S., R.S., D.R., S.R.).; Gomez Salinero JM; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY. (Y. Lin, M. Yokoyama, Y. Liu, M.S., M.G., K.C., F.G., J.M.G.S., R.S., D.R., S.R.).; Chen S; 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.).; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis. (Y. Lin, S.C., M.C.Y.).; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY (S.C.).; Shelley WC; 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.).; Yoshimoto M; 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.).; Li Calzi S; Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis. (S.L.C., M.B.G.).; 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 Birmingham (S.L.C., M.B.G.).; Murphy MP; Department of Surgery, Indiana University School of Medicine, Indianapolis. (C.-H.G., M.P.M.).; Horie K; Department of Physiology II, Nara Medical University, Kashihara, Nara, Japan (K.B., K.H.).; Grant MB; Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis. (S.L.C., M.B.G.).; 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 Birmingham (S.L.C., M.B.G.).; Schreiner R; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY. (Y. Lin, M. Yokoyama, Y. Liu, M.S., M.G., K.C., F.G., J.M.G.S., R.S., D.R., S.R.).; Redmond D; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY. (Y. Lin, M. Yokoyama, Y. Liu, M.S., M.G., K.C., F.G., J.M.G.S., R.S., D.R., S.R.).; Basile DP; Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis. (D.P.B.).; Rafii S; Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY. (Y. Lin, M. Yokoyama, Y. Liu, M.S., M.G., K.C., F.G., J.M.G.S., R.S., D.R., S.R.).; Yoder MC; 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.).; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis. (Y. Lin, S.C., M.C.Y.).; Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, PA (M.C.Y.).
Source
Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0147763 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4539 (Electronic) Linking ISSN: 00097322 NLM ISO Abbreviation: Circulation Subsets: MEDLINE
Subject
Language
English
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 ( 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.
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
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.