Abstract Radiation-induced gastrointestinal syndrome (RIGS) results from a combination of direct cytocidal effects on intestinal crypt and endothelial cells and subsequent loss of the mucosal barrier, resulting in diarrhea, microbial infection and septic shock. While growth factors, such as, R-spondin1 and KGF can protect mice from RIGS, mitigation is rare, following exposure to lethal doses of irradiation (IR). We hypothesized that IR-induced depletion and injury of intestinal stem cells (ISC) and stromal cells of the ISC niche induces RIGS. Since stromal cells provide critical growth factor/signals for ISC regeneration, we examined whether transplantation of bone marrow (BM)-derived adherent stem cells (BMASC) containing mesenchymal stem cells (MSC), endothelial progenitor cells (EPC) and macrophages would mitigate RIGS. Harvested BM cells, from C57Bl/6 mice, were cultured in MSCBM (Cambrex-Lonza) for 4 days, followed by collection of adherent cells from culture plates as BMASC. C57Bl/6 mice received a single fraction of either whole body irradiation (WBI; 8-12 Gy) or total abdominal irradiation (AIR; 16-20 Gy), followed by transplantation of BMASC (1×106 cells/mice) 24 and 72 hours after exposure to IR via tail vein injection. Irradiated controls received MSC culture medium. To evaluate the mitigating effect of myeloid cells, BMASC were fractionated with anti-CD11b-magnetic beads (MACS), followed by transplantation of CD11b+ and CD11b- BMASC cells in irradiated mice as above, respectively. Animals were observed for survival (Kaplan-Meier) and histopathological evaluation (Hematoxylin-eosin, TUNEL and BrdU immunohistochemistry). Xylose absorption test was performed to assess the functional integrity of intestinal mucosal barrier. Flow cytometry demonstrated 48% + 2.1 MSC (CD105+CD45-), 8.1% + 0.53 EPC (CD133+ CD45-) and 17.3% + 1.8 myeloid/macrophages in BMASC donor cells. In contrast to irradiated controls, 100% of the mice that received BMASC transplantation survived a lethal dose of WBI (10.4 Gy) and AIR (18Gy) (p<0.002 and p<0.004 respectively in Kaplan-Meier analysis) for up to 30 days. Transplantation of either CD11b+ myeloid cells or CD11b-CD105+ MSC could mitigate 30-40% of animals, indicating that both MSC and macrophages are necessary for RIGS mitigation. Immunohistological analysis demonstrated significant increase in proliferation rate (p<0.004), crypt depth and villi length (p<0.001) and decrease in apoptotic crypt cells (p<0.003) in transplanted animals on 3.5 days after IR. Xylose absorption was higher in these animals indicating a rapid intestinal regeneration following BMASC transplantation. In conclusion, this is the first demonstration that transplantation of BMASC could mitigate RIGS after exposure to lethal doses of IR. Further studies are underway to characterize the factors and signaling pathways responsible for RIGS mitigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1393.
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Open Access
Sep 21, 2011
Suzanne M Vercauteren + 8
