Lung Regeneration by Transplantation of Allogeneic Lung Progenitors Using a Safer Conditioning Regimen and Clinical-grade Reagents

Irit Milman Krentsis, Ran Orgad, Yangxi Zheng, Esther Bachar Lustig, Chava Rosen, Elias Shezen, Sandeep Yadav, Bar Nathansohn Levi, Miri Assayag, Neville Berkman, Harry Karmouty Quintana, Einav Shoshan, Christa Blagdon, Yair Reisner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Over the last decades, several studies demonstrated the possibility of lung regeneration through transplantation of various lung progenitor populations. Recently, we showed in mice that fetal or adult lung progenitors could potentially provide donor cells for transplantation, provided that the lung stem cell niche in the recipient is vacated of endogenous lung progenitors by adequate conditioning. Accordingly, marked lung regeneration could be attained following i.v. infusion of a single cell suspension of lung cells into recipient mice conditioned with naphthalene (NA) and 6Gy total body irradiation (TBI). As clinical translation of this approach requires the use of allogenic donors, we more recently developed a novel transplantation modality based on co-infusion of hematopoietic and lung progenitors from the same donor. Thus, by virtue of hematopoietic chimerism, which leads to immune tolerance toward donor antigens, the lung progenitors can be successfully engrafted without any need for post-transplant immune suppression. In the present study, we demonstrate that it is possible to replace NA in the conditioning regimen with Cyclophosphamide (CY), approved for the treatment of many diseases and that a lower dose of 2 GY TBI can successfully enable engraftment of donor-derived hematopoietic and lung progenitors when CY is administered in 2 doses after the stem cell infusion. Taken together, our results suggest a feasible and relatively safe protocol that could potentially be translated to clinical transplantation of lung progenitors across major MHC barriers in patients with terminal lung diseases.

Original languageAmerican English
Pages (from-to)178-188
Number of pages11
JournalStem cells translational medicine
Volume11
Issue number2
DOIs
StatePublished - Feb 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 The Author(s)..

Keywords

  • Lung progenitors
  • allogeneic
  • conditioning
  • immune suppression
  • immune tolerance
  • rejection
  • transplantation

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