Restoration of gut motility in Kit-deficient mice by bone marrow transplantation
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Interstitial cells of Cajal (ICC) play important roles in autonomic gut motility as electrical pacemakers and mediators of neural regulation of smooth muscle functions. Insufficiency of ICC has been reported in a wide range of gut dysmotilities. Thus, restoration of ICC may be a therapeutic modality in these diseases. Here we provide evidence that transplanted bone marrow (BM) cells can restore gut dysmotility in part via transdifferentiation to ICC.
Bone marrow cells obtained from Kit insufficient W/W v mice or syngeneic GFP-transgenic mice with wild-type Kit were transferred to W/W v recipients. Whole gut transit time and gastric emptying were examined 5 and 6 weeks after BM transplantation, respectively, and ICCs were identified in whole mounts, frozen sections and transmission electron immunomicroscopy of the gut smooth muscle layers using specific antibodies.
Transplantation of wild-type BM into W/W v mice significantly improved whole gut transit time and gastric emptying. Fluorescent immunohistochemistry revealed GFP+Kit+ cells in the myenteric plexus, deep muscular plexus, and submucosal plexus smooth muscle layers of the stomach, small intestine, and colon, respectively. In the whole mounts, GFP+Kit+ cells were bipolar and spindle shaped, and transmission electron immunomicroscopy showed GFP+ cells rich in mitochondria and endoplasmic reticulum between gut smooth muscle layers, suggesting the presence of GFP+ cells with morphological characteristics of ICC.
These results suggest that BM contains cells that may incorporate into ICC networks and improve dysmotility in W/W v mice. Thus, BM transplantation may become to a new therapeutic modality for gut dysmotilities due to ICC insufficiency.
KeywordsBone marrow Green fluorescent protein Interstitial cells of Cajal
Interstitial cells of Cajal
Green fluorescent protein
Fetal bovine serum
Phosphate buffered saline
The authors thank Professors Shigeko Torihashi and Masaru Okabe for providing the AIC antibody and the GFP-Tg mice, respectively. Shuji Ishii conducted most of the experiments. Shingo Tsuji was the primary investigator who planned the study. Masahiko Tsujii, Tetsuo Takehara, Sunao Kawano, and Norio Hayashi contributed to the design of the study and interpretation of the results. Tsutomu Nishida performed bone marrow transplantation. Hideki Iijima participated in the flow cytometry. Kenji Watabe participated in histopathological analyses.
The study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS; no. 18590681).
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