Myeloid Progenitors Protect Against Radiation-Induced Intestinal Injury.

Gastrointestinal mucositis is a serious complication of intensive chemotherapy and radiotherapy (XRT) resulting in severe pain, impaired nutrition and an increased susceptibility to infection. We have previously reported that a single infusion of common myeloid and granulocyte-monocyte progenitors (CMP/GMP, c-kit+Sca-1+ CD34+ CD16/32+Lin-Thy1-) protects mice against lethal challenge with bacterial or fungal pathogens following chemotherapy or myeloablative radiation. Additionally, this protection is not HLA-restricted and correlates with the tissue myeloid content. We now present our findings on the effects of CMP/GMP infusion against radiation-induced injury in the gastrointestinal mucosa and liver. Following 950 cGy irradiation, Balb/c mice (H2d) received infusions of one of the following: [1] hematopoietic stem cells (HSC, c-kit+Thy1loLin-Sca-1+); [2] freshly isolated 10,000 CMP/20,000 GMP + HSC; or [3] 500,000 mixed myeloid progenitors (MP) expanded in vitro from HSC. In all cases, the HSC were MHC-matched (H2d), and CMP/GMP were MHC mis-matched (H2b). A cohort of mice served as XRT controls. Mice were sacrificed at d+6 or d+9 post-transplantation. Gross examination of the gastrointestinal tissues showed that mice in the XRT and HSC groups had severe hemorrhagic diarrhea in contrast to the mild to moderate diarrhea observed in the groups receiving either freshly isolated CMP/GMP or the expanded MP. At both time points, histologic examination of gastrointestinal tissue from the XRT controls revealed sub-mucosal bleeding in gastric and intestinal tissue; necrosis and ulceration in the stomach; crowding of villus-proximal epithelial cells in the small intestine; ulcerative areas and small foci of inflammation in the colon; and necrosis, portal tract damage, and dilated sinusoids/central veins in the liver. In comparison, the histologic changes were significantly less dramatic in the stomachs, colons, and livers of the mice that received either freshly isolated CMP/GMP or in vitro expanded MP. In a parallel experiment, irradiated mice were transplanted with bioluminescent CMP/GMP from transgenic FVB.luc+ mice (H2q) constitutively expressing firefly luciferase. Imaging of the live mice as well as harvested organs at d+6 and d+9 post-transplantation indicated the presence of CMP/GMP in the stomach and intestine, correlating with sites of attenuated XRT damage in our histologic analysis. These findings support the observation that repletion of the myeloid progenitor pool enhances the recovery of radiation-injured mucosa, and raises the possibility that similar applications may be considered in the human clinical setting.