Genetic Tagging During Human Mesoderm Differentiation Reveals Tripotent Lateral Plate Mesodermal Progenitors

Author:

Chin Chee Jia1,Cooper Aaron R.23,Lill Georgia R.3,Evseenko Denis4,Zhu Yuhua1,He Chong Bin1,Casero David1,Pellegrini Matteo56,Kohn Donald B.35789,Crooks Gay M.71810

Affiliation:

1. Department of Pathology & Laboratory Medicine, David Geffen School of Medicine (DGSOM), Los Angeles, CA, United States

2. Molecular Biology Interdepartmental PhD Program, DGSOM University of California Los Angeles, Los Angeles, CA, United States

3. Department of Microbiology, Immunology and Molecular Genetics, DGSOM, DGSOM University of California Los Angeles, Los Angeles, CA, United States

4. Department of Orthopedic Surgery, Keck School of Medicine of University of Southern California (USC)., Los Angeles, CA, United States

5. Molecular Biology Institute (MBI), Los Angeles, CA, United States

6. Department of Molecular, Cell and Development Biology, DGSOM University of California Los Angeles, Los Angeles, CA, United States

7. Department of Pediatrics, DGSOM University of California Los Angeles, Los Angeles, CA, United States

8. Broad Stem Cell Research Center (BSCRC), DGSOM University of California Los Angeles, Los Angeles, CA, United States

9. Jonsson Comprehensive Cancer Center (JCCC), DGSOM University of California Los Angeles, Los Angeles, CA, United States

10. Department of Pathology & Laboratory Medicine, DGSOM University of California Los Angeles, Los Angeles, CA, United States

Abstract

Abstract Although clonal studies of lineage potential have been extensively applied to organ specific stem and progenitor cells, much less is known about the clonal origins of lineages formed from the germ layers in early embryogenesis. We applied lentiviral tagging followed by vector integration site analysis (VISA) with high-throughput sequencing to investigate the ontogeny of the hematopoietic, endothelial and mesenchymal lineages as they emerge from human embryonic mesoderm. In contrast to studies that have used VISA to track differentiation of self-renewing stem cell clones that amplify significantly over time, we focused on a population of progenitor clones with limited self-renewal capability. Our analyses uncovered the critical influence of sampling on the interpretation of lentiviral tag sharing, particularly among complex populations with minimal clonal duplication. By applying a quantitative framework to estimate the degree of undersampling we revealed the existence of tripotent mesodermal progenitors derived from pluripotent stem cells, and the subsequent bifurcation of their differentiation into bipotent endothelial/hematopoietic or endothelial/mesenchymal progenitors.

Funder

CIRM Basic Biology Award

CIRM Training Grant

International Fulbright Science and Technology Award

National Research Service Award

NIH

DOD

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,Molecular Medicine

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