@article{849b41f2bab9431f8dfaa0a83095d8d4,
title = "Generation of complex bone marrow organoids from human induced pluripotent stem cells",
abstract = "The human bone marrow (BM) niche sustains hematopoiesis throughout life. We present a method for generating complex BM-like organoids (BMOs) from human induced pluripotent stem cells (iPSCs). BMOs consist of key cell types that self-organize into spatially defined three-dimensional structures mimicking cellular, structural and molecular characteristics of the hematopoietic microenvironment. Functional properties of BMOs include the presence of an in vivo-like vascular network, the presence of multipotent mesenchymal stem/progenitor cells, the support of neutrophil differentiation and responsiveness to inflammatory stimuli. Single-cell RNA sequencing revealed a heterocellular composition including the presence of a hematopoietic stem/progenitor (HSPC) cluster expressing genes of fetal HSCs. BMO-derived HSPCs also exhibited lymphoid potential and a subset demonstrated transient engraftment potential upon xenotransplantation in mice. We show that the BMOs could enable the modeling of hematopoietic developmental aspects and inborn errors of hematopoiesis, as shown for human VPS45 deficiency. Thus, iPSC-derived BMOs serve as a physiologically relevant in vitro model of the human BM microenvironment to study hematopoietic development and BM diseases.",
author = "Stephanie Frenz-Wiessner and Fairley, {Savannah D.} and Maximilian Buser and Isabel Goek and Kirill Salewskij and Gustav Jonsson and David Illig and {zu Putlitz}, Benedicta and Daniel Petersheim and Yue Li and Chen, {Pin Hsuan} and Martina Kalauz and Raffaele Conca and Michael Sterr and Johanna Geuder and Yoko Mizoguchi and Megens, {Remco T.A.} and Linder, {Monika I.} and Daniel Kotlarz and Martina Rudelius and Penninger, {Josef M.} and Carsten Marr and Christoph Klein",
note = "Funding Information: We are grateful to all team members of our laboratory and core facilities for stimulating discussion and help, in particular M. Tatematsu, M. Rohlfs and J. Bibus. We would like to thank S. Dietzel and A. Thomae from the Core Facility Bioimaging of the Biomedical Center of the LMU for excellent technical assistance. We thank N. Drexler and T. Heuser from the Electron Microscopy Facility and M. Grivej from the Histology Facility at VBCF, which acknowledges funding from the Austrian Federal Ministry of Education, Science and Research and the City of Vienna. We thank M. Drukker for providing the HMGU1 iPS cell line. We thank W. Enard for providing the 29B5 and 12C2 iPS cell lines. We thank L. Shultz (The Jackson Laboratory) for providing NSG-HLA-DQ8 mice. We would like to thank G. Piontek at the Institute of Pathology, LMU Munich and T. Walzthoeni at the Core Facility Genomics, Helmholtz Munich for technical assistance. This work has been supported by the Reinhard Frank-Stiftung, the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; SFB914/A08, TRR332/B01, CRC1123/Z1, INST 86/1909-1, INST409/150-1FUGG, EN 1093/5-1, project number 458247426), the German Center for Infection Research (DZIF, TTU07.820), the Else Kr{\"o}ner-Fresenius-Stiftung, the Hector Foundation, the Leona M. and Harry B. Helmsley Charitable Trust, the VEO-IBD-Consortium and the National Institute of Health (RC2 VEO-IBD 5RC2DK122532-02), as well as institutional funds by the Dr. von Hauner Children{\textquoteright}s Hospital. C.M. has received funding from the European Research Council (ERC) und the European Union{\textquoteright}s Horizon 2020 research and innovation program (grant agreement no. 8664111) and acknowledges support from the Hightech Agenda Bayern. The laboratory of J.M.P. received funding from the Austrian Academy of Sciences, the Medical University of Vienna, the Fundacio La Marato de TV3 (202125-31), the T. von Zastrow foundation, the Canada 150 Research Chairs Program F18-01336, the Allen Distinguished Investigator program, the Leducq Foundation (Transatlantic Network of Excellence grant {\textquoteleft}ReVAMP—Recalibrating Mechanotransduction in Vascular Malformations{\textquoteleft}, 21CVD03), the Diamond-Blackfan-Anemia Fundraising ( dbaexperiment.org ) and the Innovative Medicines Initiative?2 Joint Undertaking (no. 101005026). This Joint Undertaking receives support from the European Union{\textquoteright}s Horizon 2020 research and innovation program and EFPIA (European Federation of Pharmaceutical Industries and Associations). J.M.P. also gratefully acknowledges funding by the German Federal Ministry of Education and Research (BMBF) under the project {\textquoteleft}Microbial Stargazing—Erforschung von Resilienzmechanismen von Mikroben und Menschen{\textquoteright} (Ref. 01KX2324). Schemes in Figs. – and Extended Data Figs. and were created with BioRender.com . Publisher Copyright: {\textcopyright} The Author(s) 2024.",
year = "2024",
month = jan,
day = "1",
doi = "10.1038/s41592-024-02172-2",
language = "English",
journal = "Nature Methods",
issn = "1548-7091",
publisher = "Nature Publishing Group",
}