Post-radiation pulmonary epithelial regeneration from transplanted adult stem cells

Abstract

7022 Background: Pneumonitis and pulmonary damage are common toxicities of chest radiation therapy (RT), which may be reduced by transplantation of stem cells that differentiate into pulmonary epithelium. Multipotent Adult Progenitor Cells (MAPC) are adult bone marrow (BM) derived cells, which after IV injection in NOD-SCID mice, differentiate into epithelial and hematopoietic tissues (Nature 418:41). Here we tested the ability of mouse (m) MAPC to regenerate epithelia after RT, in Fanconi Anemia C (FAC) mouse model, which inherently has DNA repair defects and is over sensitive to DNA-cross linking agents. Methods: One million, enhanced-green fluorescent protein (eGFP)- expressing, wild-type mMAPC were injected IV in FAC mice, 4–24 hours after 7.5 Gy (followed by mitomycin C {MMC} 0.1mg/kg/week X 4 in a subset) or 11 Gy RT. Non-eGFP expressing BM was co-transplanted after myeloablative (11 Gy) RT. BM, lungs, intestine and liver of the recipients were analyzed 3–10 months post-transplant for eGFP+ cells and epithelial (CK+) or hematopoietic (CD45+) differentiation using flowcytometry (BM) & immunohistochemistry. Control FAC mice were identically treated but without MAPC. Results: MAPC engraftment (>1% eGFP+ cells) was absent in all control mice. Following 7.5 Gy RT, autologous BM recovery occurred in all (N=10) mice and 1 mouse had 2.7% donor-derived hematopoietic (eGFP+/CD45+) cells after MMC. In both recipients of 11Gy RT, analyzed 9–10 months post-transplant, 5–7% of all CD45+ BM cells were donor MAPC-derived. No donor MAPC-derived epithelial cells were seen in the intestine or liver. However, lungs of most recipients had clusters of donor MAPC-derived epithelial cells, estimated to comprise 1–8% of all pulmonary epithelial cells, consistent with homing of MAPC in lungs following IV injection and their epithelial differentiation in the post-radiation, regenerative, pulmonary micro- environment. The highest degree of MAPC-derived pulmonary regeneration was seen following 11Gy RT that was persistent at 10 months post- transplant. Conclusions: Following radiation, IV injected mMAPC differentiate into hematopoietic and pulmonary epithelial cells that persist long-term. MAPC transplantation has the potential for reducing radiation-induced pulmonary toxicity. No significant financial relationships to disclose.