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1165 Hematopoietic Stem Cells Develop in the Absence of Endothelial Cadherin 5 Expression

Hematopoietic Stem and Progenitor Biology
Program: Oral and Poster Abstracts
Session: 501. Hematopoietic Stem and Progenitor Biology: Poster I
Saturday, December 5, 2015, 5:30 PM-7:30 PM
Hall A, Level 2 (Orange County Convention Center)

Heidi Anderson1*, Taylor Patch2*, Pavan Reddy3*, Elliott Hagedorn3*, Owen J. Tamplin, PhD4, Daniel E. Bauer, M.D., Ph.D.5, Barry H. Paw, M.D., Ph.D.6, Dietmar Vestweber7*, Leonard I. Zon, M.D8, Stuart H. Orkin, M.D.9, George Q. Daley, MD, PhD10 and Dhvanit I. Shah, Ph.D.11,12

1Brigham and Women's Hospital, Harvard Medical School, Boston, MA
2Brigham and Women's Hospital, Boston, MA
3Boston Children's Hospital, Boston, MA
4Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Boston, MA
5Pediatric Hematology-Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
6Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
7Max Plank Institute for Molecular Biomedicine, Muenster, Germany
8Stem Cell Program and Division of Hematology/Oncology, Howard Hughes Medical Institute, Boston Children's Hospital/Harvard Medical School, Boston, MA
9Department of Pediatric Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, HHMI, Boston, MA
10Hematology/Oncology, Boston Children's Hospital, Boston, MA
11Hematology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
12Harvard Stem Cell Institute, Cambridge, MA

Rare endothelial cells in the aorta-gonad-mesonephros (AGM) transition into hematopoietic stem cells (HSCs) during embryonic development. Lineage tracing experiments indicate that HSCs emerge from Cadherin 5 (Cdh5, VE-cadherin)+ endothelial precursors, and isolated populations of Cdh5+ cells from mouse embryos and embryonic stem (ES) cells can be differentiated into hematopoietic cells. Cdh5 has also been widely implicated as a marker of AGM-derived hemogenic endothelial cells. Since Cdh5-/- mice embryos die before the first HSCs emerge, it is unknown if Cdh5 has a direct role in HSC emergence. Our previous genetic screen yielded malbec (mlbbw306), a zebrafish mutant for cdh5, with normal embryonic and definitive blood. Utilizing time-lapse imaging, parabiotic surgical pairing of zebrafish embryos, and blastula transplantation assays, we show that HSCs emerge, migrate, engraft, and differentiate in the absence of cdh5 expression. By tracing Cdh5-/-GFP+/+ cells in chimeric mice, we demonstrated that Cdh5-/- GFP+/+ HSCs emerging from E10.5 and E11.5 AGM or derived from E13.5 fetal liver not only differentiate into hematopoietic colonies but also engraft and reconstitute multi-lineage adult blood. These data establish that Cdh5, a marker of hemogenic endothelium in the AGM, is dispensable for the transition of hemogenic endothelium to HSCs.

Disclosures: Bauer: Biogen: Research Funding ; Editas Medicine: Consultancy . Zon: FATE Therapeutics: Employment , Equity Ownership , Membership on an entity’s Board of Directors or advisory committees , Other: Founder ; Scholar Rock: Employment , Equity Ownership , Membership on an entity’s Board of Directors or advisory committees , Other: Founder . Orkin: Editas Medicine: Membership on an entity’s Board of Directors or advisory committees ; Biogen: Research Funding ; Pfizer: Research Funding ; Sangamo Biosciences: Consultancy .

*signifies non-member of ASH