Multi-lineage Lung Regeneration by Stem Cell Transplantation across Major Genetic Barriers

• Published in: Cell reports (Cambridge) Vol. 30; no. 3; pp. 807 - 819.e4
• Main Authors: Hillel-Karniel, Carmit, Rosen, Chava, Milman-Krentsis, Irit, Orgad, Ran, Bachar-Lustig, Esther, Shezen, Elias, Reisner, Yair
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.01.2020; Elsevier
• Subjects: adult mouse lung; Adult Stem Cells - cytology; allogeneic transplantation; Animals; Cell Lineage - genetics; Cell Self Renewal; Chimera; fetal mouse lung; Fetus - cytology; Hematopoiesis; Hematopoietic Stem Cells - cytology; Immune Tolerance; Lung - embryology; Lung - physiology; lung chimerism; Mice, Inbred C57BL; mouse bone marrow; Regeneration - genetics; Stem Cell Transplantation; Tissue Donors; tolerance induction; Transplantation Conditioning; lung chimerism; adult mouse lung; allogeneic transplantation; tolerance induction; mouse bone marrow; fetal mouse lung
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.12.058

Induction of lung regeneration by transplantation of lung progenitor cells is a critical preclinical challenge. Recently, we demonstrated that robust lung regeneration can be achieved if the endogenous stem cell niches in the recipient’s lung are vacated by sub-lethal pre-conditioning. However, overcoming MHC barriers is an additional requirement for clinical application of this attractive approach. We demonstrate here that durable tolerance toward mis-matched lung progenitors and their derivatives can be achieved without any chronic immune suppression, by virtue of co-transplantation with hematopoietic progenitors from the same donor. Initial proof of concept of this approach was attained by transplantation of fetal lung cells comprising both hematopoietic and non-hematopoietic progenitors. Furthermore, an even higher rate of blood and epithelial lung chimerism was attained by using adult lung cells supplemented with bone marrow hematopoietic progenitors. These results lay the foundation for repair of lung injury through a procedure akin to bone marrow transplantation. [Display omitted] •Tolerance to mis-matched lung progenitors is achieved without chronic immune suppression•Tolerance is induced by intravenous transplantation of lung and hematopoietic cells•Engraftment of donor-derived progenitors is observed in different lung cell linages•Lung regeneration is achieved through a procedure akin to bone marrow transplantation Hillel-Karniel et al. demonstrate that co-transplantation of lung and hematopoietic progenitors from the same donor in preconditioned mice allows the induction of durable multi-lineage lung chimerism and lung regeneration across major genetic barriers. These results lay the foundation for lung regeneration through a simple procedure akin to bone marrow transplantation.