Purpose: Bone marrow (BM) cells could repopulate damaged tissue and contribute to repair in non-hematopoietic tissues. Our previous observations demonstrated that the mitigating effect to acute repair of intestine was achieved through paracrine mediators released by BM cells. Maximal appearance of BM cells within lamina propria, however, occurred long after intestine mucosa recovered from radiation damage. Recent studies revealed cell fusion between BM and somatic cells were enhanced by chronic inflammation. There was a significant role of BM cells in triggering fibrotic responses and contribute to liver and renal fibrosis. We would like to explore the association between cell fusion and fibrosis within a murine model of whole body irradiation (WBI) and BM transplantation (BMT). Materials and Methods: Using gender-mismatched BM transplantation (BMT and BMT from green fluorescence transgenic mice donors, we quantified and characterized the fusion phenomenon within intestine of mice after irradiation. The proliferating index was evaluated within intestine and in co-culture system of mouse BM and human intestine stroma cells. By using pravastatin, an HMG Co-A reductase inhibitor, to block fibrosis in mice after WBI, we evaluated the proliferation and fusion phenomenon by histology and biochemical test. The fusion ratio, fusion signaling proteins (macrophage fusion receptor and CD47) and fibrosis markers (CCN2, fibronectin, collagen) were examined. Fibrosis score within intestine and mucosa lysates of mice after WBI+BMT were evaluated after Clodronate liposome to deplete macrophage/myelomonocytic cells. Results: Most BM cells fused with intestine stromal cells after BMT to mice after WBI. BM derived macrophage/myelomonocytic cells contributed mostly to the fusion phenomenon. Proliferation index within intestine increased maximally at 6 weeks after WBI+BMT when BM derived cells within lamina propria reached a plateau. The maximal fusion phenomenon occurred before significant level of fibrosis appeared within intestine of mice after WBI+BMT. Intestine mucosa lysates from mice receiving clodronate after WBI and BMT revealed decreased cell fusion and fibrosis in histology as well as in biochemical examination. Pravastatin suppressed the cell fusion protein expression, fusion phenomenon and the proliferation index within fused cells. Conclusions: BM derived macrophage/myelo-monocytic cells fuse with intestine stromal cells and induce proliferation of BM derived cells within lamina propria of intestine. The fusion phenomenon is associated with chronic intestine fibrosis after radiation. Intestine fibrosis may be ameliorated by depleting macrophage/myelomonocytic cells. The fusion phenomenon can be diminished by antifibrosis strategy. Fusion between BM and intestine stromal cells contributes to chronic intestine fibrosis.
Date:
2012-03
Relation:
Radiotherapy and Oncology. 2012 Mar;102(Suppl. 1):S66-S67.
