Adoptive transfer of mesenchymal stromal cells accelerates intestinal epithelium recovery of irradiated mice in an interleukin-6-dependent manner

Abstract

Background aims. Apoptosis of radiosensitive cells in the bone marrow and gut is a serious, at times life-threatening, complication arising from radiation exposure. Methods. We investigated whether adoptive transfer of allogeneic bone marrow-derived mesenchymal stromal cells (MSC) could exert cytoprotective and life-sparing effects in a mouse model of sublethal total body irradiation (TBI). Results. We demonstrated that a single intraperitoneal injection of C57Bl/6 MSC given to major histocompatibility complex (MHC)-mismatched Balb/c mice within 24 h of sublethal TBI significantly reduced mortality in a dose-dependent manner. Histologic analysis and Ki67 immunostaining of jejunum sections collected 3 and 6 days post-TBI indicated that MSC protected the gastrointestinal epithelium from TBI-induced damage and significantly accelerated recovery of the gut by stimulating proliferation of the crypt cell pool. Using interleukin-6^–/– (IL-6) MSC, we demonstrated that IL-6 expressed by MSC played a role in gastrointestinal epithelium regeneration. Conclusions. Our results suggest that allogeneic MHC-mismatched MSC may be exploited to reduce gastrointestinal complications and mortality arising from ionizing radiation exposure.

Key Words::

• gastrointestinal epithelium
• interleukin-6
• irradiation
• mesenchymal stromal cell
• regeneration

Acknowledgments

We thank the radiation technologists Sevelin Stanchev, Remo Adorante and Sophie Jodoin of the radio-oncology department of the Jewish General Hospital of Montreal for performing the irradiation, and Micheline Fortin form the histology platform of the Institute de Recherche en Immunologie et Cancérologie of Montreal for performing histologic sections and staining. A special thanks to Floran François for his help with image analysis.

Support and financial disclosure declaration: Moïra François was supported by the F. Banting and C. Best Doctoral Bursary of the Canadian Institute of Health Research (CIHR).This work was supported by CIHR grant MOP-15017. Jacques Galipeau is a Georgia Distinguished Cancer Scholar.

The authors of this manuscript have no conflicts of interest to disclose.