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

Author:

Milman Krentsis Irit12ORCID,Orgad Ran2,Zheng Yangxi1,Bachar Lustig Esther12,Rosen Chava123,Shezen Elias12,Yadav Sandeep1,Nathansohn Levi Bar2,Assayag Miri4,Berkman Neville4,Karmouty Quintana Harry5,Shoshan Einav1,Blagdon Christa1,Reisner Yair126

Affiliation:

1. Department of Stem Cell Transplantation and Cell Therapy, MD Anderson Cancer Center, Houston, TX, USA

2. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

3. Department of Neonatology, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tal-Hashomer, Israel

4. Pulmonary Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

5. University of Texas Health Science Center at Houston, Department of Biochemistry and Molecular Biology & Divisions of Critical Care, Pulmonary and Sleep Medicine, Houston, TX, USA

6. CPRIT Scholar in Cancer Research, Houston, TX, USA

Abstract

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.

Funder

Cystic Fibrosis Foundation

Cancer Prevention and Research Institute of Texas

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,General Medicine

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