BMP Antagonists Secreted by Mesenchymal Stromal Cells Improve Colonic Organoid Formation: Application for the Treatment of Radiation-induced Injury.

Publisher: SAGE Publishing Country of Publication: United States NLM ID: 9208854 Publication Model: Print Cited Medium: Internet ISSN: 1555-3892 (Electronic) Linking ISSN: 09636897 NLM ISO Abbreviation: Cell Transplant Subsets: MEDLINE

Publication: 2017- : Thousand Oaks, CA : SAGE Publishing
Original Publication: Elmsford, New York : Pergamon Press, c1992-

Bone Morphogenetic Proteins/*antagonists & inhibitors ; Colon/*growth & development ; Mesenchymal Stem Cells/*metabolism ; Organoids/*growth & development ; Radiation Injuries/*therapy; Animals ; Bone Morphogenetic Proteins/metabolism ; Cell Differentiation/radiation effects ; Cell Proliferation/radiation effects ; Colon/radiation effects ; Epithelial Cells/metabolism ; Epithelial Cells/radiation effects ; Green Fluorescent Proteins/metabolism ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Mucous Membrane/pathology ; Mucous Membrane/radiation effects ; Radiation, Ionizing ; Time Factors

Radiation therapy is crucial in the therapeutic arsenal to cure cancers; however, non-neoplastic tissues around an abdominopelvic tumor can be damaged by ionizing radiation. In particular, the radio-induced death of highly proliferative stem/progenitor cells of the colonic mucosa could induce severe ulcers. The importance of sequelae for patients with gastrointestinal complications after radiotherapy and the absence of satisfactory management has opened the field to the testing of innovative treatments. The aim of this study was to use adult epithelial cells from the colon, to reduce colonic injuries in an animal model reproducing radiation damage observed in patients. We demonstrated that transplanted in vitro-amplified epithelial cells from colonic organoids (ECO) of C57/Bl6 mice expressing green fluorescent protein implant, proliferate, and differentiate in irradiated mucosa and reduce ulcer size. To improve the therapeutic benefit of ECO-based treatment with clinical translatability, we performed co-injection of ECO with mesenchymal stromal cells (MSCs), cells involved in niche function and widely used in clinical trials. We observed in vivo an improvement of the therapeutic benefit and in vitro analysis highlighted that co-culture of MSCs with ECO increases the number, proliferation, and size of colonic organoids. We also demonstrated, using gene expression analysis and siRNA inhibition, the involvement of bone morphogenetic protein antagonists in MSC-induced organoid formation. This study provides evidence of the potential of ECO to limit late radiation effects on the colon and opens perspectives on combined strategies to improve their amplification abilities and therapeutic effects.

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Keywords: BMP antagonists; co-transplantation; colonic epithelial cells; mesenchymal stromal cells; radiotherapy side effects

0 (Bone Morphogenetic Proteins)
147336-22-9 (Green Fluorescent Proteins)

Date Created: 20201028 Date Completed: 20210812 Latest Revision: 20210812

20221213

PMC7784604

10.1177/0963689720929683

33108903