Studies of the route of administration and role of conditioning with radiation on unrelated allogeneic mismatched mesenchymal stem cell engraftment in a nonhuman primate model

Abstract

Objective The aim of this study was to examine the effects of the route of administration [intrabone marrow (IBM) vs intravenous (IV)] and the role of conditioning with irradiation in optimizing mesenchymal stem cell (MSC) transplantation. Materials and Methods To determine if irradiation resulted in depletion of colony-forming unit fibroblasts (CFU-F), which might favor the engraftment of donor MSC, the number of CFU-Fs was assayed from animals receiving either hemibody irradiation (HBI) or total body irradiation (TBI). Results TBI resulted in a marked reduction of CFU-F numbers that spontaneously resolved, whereas animals receiving HBI did not experience depletion of CFU-F. Animals receiving MSC grafts by the IV route had higher numbers of marrow CFU-F. MSC were transduced using retroviral vectors encoding the neomycin resistance gene (Neo R) and a second gene encoding either the human soluble tumor necrosis factor receptor (hsTNFRII) or β-galactosidase (β-Gal). MSCs were administered by either the IV or IBM route to animals receiving HBI. The Neo R transgene was detectable in hematopoietic tissues of all animals and nonhematopoietic tissues in a single animal. Evidence of transgene expression was documented by detection of β-Gal + cells in BM smears and transiently elevated serum levels of hsTNFRII. Conclusion These studies indicate that 1) MSC possess the ability to engraft and persist in an unrelated mismatched allogeneic hosts; 2) 250-cGy HBI did not favor engraftment of MSC; 3) the IBM route was not more effective than the IV route in delivering MSC grafts; and 4) transplanted MSC preferentially localized to the marrow rather than nonhematopoietic tissues.