Page 134 - 2021_05-Haematologica-web

Ferrata Storti Foundation
Hematopoiesis
A 3D iPSC-differentiation model identifies interleukin-3 as a regulator of early human hematopoietic specification
Mania Ackermann,1,2 Kathrin Haake,1,2 Henning Kempf,2,3,4 Paul Kaschutnig,5 Anna-Carina Weiss,6 Ariane H.H. Nguyen,1,2 Markus Abeln,7 Sylvia Merkert,2,3 Mark Phillip Kühnel,8,9 Dorothee Hartmann,10 Danny Jonigk,2,8,9
Thomas Thum,2,10 Andreas Kispert,6 Michael D. Milsom5
Haematologica 2021 Volume 106(5):1354-1367
1Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany; 2REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany; 3Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany; 4Department of Stem Cell Discovery, Novo Nordisk A/S, Maaloev, Denmark; 5German Cancer Research Center (DKFZ), Division of Experimental Hematology and Heidelberg Institute for Stem Cell Technology (HI-STEM), Heidelberg, Germany; 6Institute of Molecular Biology, Hannover Medical School, Hannover, Germany; 7Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany; 8Institute for Pathology, Hannover Medical School, Hannover, Germany; 9Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research, Hannover, Germany and 10Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
ABSTRACT
Hematopoietic development is spatiotemporally tightly regulated by defined cell-intrinsic and extrinsic modifiers. The role of cytokines has been intensively studied in adult hematopoiesis; however, their role in embryonic hematopoietic specification remains largely unexplored. Here, we used induced pluripotent stem cell (iPSC) technology and estab- lished a 3-dimensional (3D), organoid-like differentiation system (“hemanoid”) maintaining the structural cellular integrity to evaluate the effect of cytokines on embryonic hematopoietic development. We show that defined stages of early human hematopoietic development were reca- pitulated within the generated hemanoids. We identified KDR+/CD34high/CD144+/CD43–/CD45– hemato-endothelial progenitors (HEP) forming organized, vasculature-like structures and giving rise to CD34low/CD144–/CD43+/CD45+ hematopoietic progenitor cells. We demon- strate that the endothelial to hematopoietic transition of HEP is dependent on the presence of interleukin 3 (IL-3). Inhibition of IL-3 signaling blocked hematopoietic differentiation and arrested the cells in the HEP stage. Thus, our data suggest an important role for IL-3 in early human hematopoiesis by supporting the endothelial to hematopoietic transition of HEP and high- light the potential of a hemanoid-based model to study human hematopoi- etic development.
Introduction
Different cell-intrinsic and extrinsic factors direct the specification of early meso- dermal progenitor cells towards hematopoietic stem cells (HSC), which arise in the aorta-gonad-mesonephros (AGM) region, mature in the fetal liver and finally home and reside in the bone marrow. This process is spatiotemporally tightly regulated and proceeds through two distinct stages: a primitive and a definitive hematopoi- etic program.1 While embryonic macrophages and nucleated red blood cells are generated early in development in the first wave of primitive hematopoiesis, lym- phoid cells, definitive erythro-myeloid progenitors and long-term repopulating
and Nico Lachmann1,2
Correspondence:
NICO LACHMANN
lachmann.nico@mh-hannover.de
Received: May 28, 2019. Accepted: March 25, 2020. Pre-published: April 23, 2020.
https://doi.org/10.3324/haematol.2019.228064
©2021 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
1354
haematologica | 2021; 106(5)
ARTICLE