Inducible Forward Programming of Human Pluripotent Stem Cells to Hemato-endothelial Progenitor Cells with Hematopoietic Progenitor Potential

Lucas Lange; Dirk Hoffmann; Adrian Schwarzer; Teng-Cheong Ha; Friederike Philipp; Daniela Lenz; Michael Morgan; Axel Schambach

doi:10.1016/j.stemcr.2019.11.005

Inducible Forward Programming of Human Pluripotent Stem Cells to Hemato-endothelial Progenitor Cells with Hematopoietic Progenitor Potential

Stem Cell Reports. 2020 Jan 14;14(1):122-137. doi: 10.1016/j.stemcr.2019.11.005. Epub 2019 Dec 12.

Authors

Lucas Lange¹, Dirk Hoffmann¹, Adrian Schwarzer², Teng-Cheong Ha¹, Friederike Philipp³, Daniela Lenz¹, Michael Morgan¹, Axel Schambach⁴

Affiliations

¹ Institute of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; REBIRTH Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany.
² Institute of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; REBIRTH Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany; Department of Hematology, Oncology, Hemostasis and Stem Cell Transplantation, Hannover Medical School, Hannover 30625, Germany.
³ Institute of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; REBIRTH Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany; Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Hannover, Germany.
⁴ Institute of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; REBIRTH Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 02115 Boston, MA, USA. Electronic address: schambach.axel@mh-hannover.de.

Abstract

Induced pluripotent stem cells (iPSCs) offer a promising platform to model early embryonic developmental processes, to create disease models that can be evaluated by drug screens as well as proof-of-concept experiments for regenerative medicine. However, generation of iPSC-derived hemato-endothelial and hematopoietic progenitor cells for these applications is challenging due to variable and limited cell numbers, which necessitates enormous up-scaling or development of demanding protocols. Here, we unravel the function of key transcriptional regulators SCL, LMO2, GATA2, and ETV2 (SLGE) on early hemato-endothelial specification and establish a fully inducible and stepwise hemato-endothelial forward programming system based on SLGE-regulated overexpression. Regulated induction of SLGE in stable SLGE-iPSC lines drives very efficient generation of large numbers of hemato-endothelial progenitor cells (CD144⁺/CD73^-), which produce hematopoietic progenitor cells (CD45⁺/CD34⁺/CD38^-/CD45RA^-/CD90⁺/CD49f⁺) through a gradual process of endothelial-to-hematopoietic transition (EHT).

Keywords: endothelial-to-hematopoietic transition; forward programming; hemato-endothelial progenitors; hematopoietic development; hematopoietic progenitor cells; hemogenic endothelium; human induced pluripotent stem cells; transcription factors.

Publication types

Research Support, Non-U.S. Gov't