Generation of transgene-free hematopoietic stem cells from human induced pluripotent stem cells

Olivier Piau (1, 2) , Mathias Brunet-Manquat (2) , Laurence Petit (3) , Bruno L'Homme (4) , Brigitte Birebent (5) , Christine Linard (6) , Laetitia Moeckes (7) , Thomas Zuliani (8, 9, 10) , Hélène Lapillonne (11, 12) , Marc Benderitter (13, 6) , Luc Douay (2) , Alain Chapel (6) , Laurence Guyonneau-Harmand (14, 15, 16) , Thierry Jaffredo (17, 1, 16)

1 LBD - Laboratoire de Biologie du Développement [IBPS]
2 CRSA - Centre de Recherche Saint-Antoine
3 IBPS - Institut de Biologie Paris Seine
4 IRSN/PSE-SANTE/SERAMED/LRAcc - Laboratoire de Radiobiologie des expositions accidentelles
5 Etablissement Français du Sang [Île-de-France Mondor]
6 IRSN/PSE-SANTE/SERAMED/LRMed - Laboratoire de Radiobiologie des expositions médicales
7 Unité d’Ingénierie Cellulaire [EFS, Nantes]
8 Unité de thérapie cellulaire et génique
9 Laboratoire d'immunodermatologie
10 CIC biothérapies CBT 0503 [Nantes]
11 CHU Trousseau [APHP]
12 Hôpitaux universitaires Est parisien [AP-HP]
13 IRSN/PSE-SANTE - Pôle Santé Environnement - Direction Santé
14 CHU Saint-Antoine [AP-HP]
15 EFS Ile de France, Unité d’Ingénierie et de Thérapie Cellulaire, Créteil, F-94017, France.
16 SU - Sorbonne Université
17 LBD - Laboratoire de Biologie du Développement

Hematopoietic stem cells (HSCs) are the rare cells responsible for the lifelong curative effects of hematopoietic cell (HC) transplantation. The demand for clinical-grade HSCs has increased significantly in recent decades, leading to major difficulties in treating patients. A promising but not yet achieved goal is the generation of HSCs from pluripotent stem cells. Here, we have obtained vector- and stroma-free transplantable HSCs by differentiating human induced pluripotent stem cells (hiPSCs) using an original one-step culture system. After injection into immunocompromised mice, cells derived from hiPSCs settle in the bone marrow and form a robust multilineage, hematopoietic population that can be serially transplanted. Single cell RNA sequencing shows that this repopulating activity is due to a hematopoietic population that is transcriptionally similar to human embryonic aorta-derived HSCs. Overall, our results demonstrate the generation of HSCs from hiPSC and will help identify key regulators of HSC production during human ontogeny.

Domains: Life Sciences [q-bio]

Olivier Piau, Mathias Brunet-Manquat, Laurence Petit, Bruno L'Homme, Brigitte Birebent, et al.. Generation of transgene-free hematopoietic stem cells from human induced pluripotent stem cells. Cell Stem Cell, 2023, 30 (12), pp.1610-1623.e7. ⟨10.1016/j.stem.2023.11.002⟩. ⟨hal-04355216⟩