Elsevier

Radiotherapy and Oncology

Volume 105, Issue 3, December 2012, Pages 371-377
Radiotherapy and Oncology

Experimental radiobiology
Bone marrow transplantation rescues intestinal mucosa after whole body radiation via paracrine mechanisms

https://doi.org/10.1016/j.radonc.2012.10.005Get rights and content

Abstract

Purpose

Our previous study reveals bone marrow transplantation (BMT) recruits host marrow-derived myelomonocytic cells to radiation-injured intestine, enhancing stromal proliferation, leading secondarily to epithelial regeneration. In this study, we propose BMT ameliorates intestinal damage via paracrine mechanisms.

Materials and methods

Angiogenic cytokines within the intestinal mucosa of mice after whole body irradiation (WBI) with or without BMT were measured by cytokine array and ELISA. BM conditioned medium (BMCM) with or without treatment with neutralizing antibodies to angiogenic cytokines were continuously infused into mice for three days after radiation. Carrageenan was used to deplete myelomonocytic cells of mice.

Results

BMT increased VEGF, bFGF and other angiogenic and chemotactic cytokines in the intestinal mucosa within 24 h after WBI. Infusion of BMCM ameliorated radiation-induced intestinal damage with improved stromal activity and prolonged survival of mice. Neutralization of bFGF, PDGF and other angiogenic cytokines within BMCM abolished the mitigating effect to the intestine. Pretreatment of carrageenan to recipient mice reversed some of the cytokine levels, including VEGF, bFGF and IGF within the intestinal mucosa after BMT.

Conclusions

Our result suggests BMT recruits host myelomonocytic cells and enhances intestinal stroma proliferation after radiation by secreting cytokines enhancing angiogenesis and chemotaxis. Host myelomonocytic cells further uplift the paracrine effect to enhance intestinal mucosal recovery.

Section snippets

Animals

Mice were housed at the animal care facility of the NHRI (Tainan, Taiwan). The facility was approved by the National Association for the Accreditation of Laboratory Animal Care, Taiwan, and was maintained in accordance with the regulations and standards of the NHRI Animal Council’s procedural and ethical guidelines. C57Bl/6 mice, 8–12 weeks old, were purchased from the National Laboratory Animal Center (NLAC).

Radiation, BMT and tissue preparation

WBI of 13 Gy was delivered using a linear accelerator (Philip SL 75-5), at a dose rate

BMCM alone may improve the intestinal survival of mice from radiation damage

According to our previous observations [6], we postulated that cytokines secreted from BM cells, either exogenously transplanted or endogenously from host, contribute to intestinal regeneration after radiation. We used conditioned medium from primary BM cell cultures to demonstrate the paracrine effect of BM cells on the intestine. The amount of each cytokine in the concentrated BM conditioned medium (BMCM) was controlled by ELISA assays (bFGF: 46.61 ± 8.77, IGF:1138.54 ± 15.56, VEGF: 274.93 ± 21.93,

Discussion

The present study demonstrated a mechanism for the engagement of BM cells in the repair of radiation damage to the intestinal mucosa. The physiological response to intestinal injury has suggested that replacement of dead cells might depend either on reentry into the cell cycle of differentiated cells surviving injury or on the contribution of BM-derived or resident stem cells. However, it was a rare event of BM cells homeing in to the intestine and replacing damaged epithelial or stromal cells

Acknowledgments

We thank Dr. Helen H.W. Chen for administrative support and Mr. Hsin-Chun Chang for technical help. This study was supported by Grant NSC 97-2321-B-400-004-MY2 and NSC100-2314-B-400-001 – from National Science Council, Taipei, Taiwan.

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