Adipose mesenchymal stromal cells response to ionizing radiation

Osama Muhammad Maria; Slawomir Kumala; Mitra Heravi; Alasdair Syme; Nicoletta Eliopoulos; Thierry Muanza

doi:10.1016/j.jcyt.2015.12.001

Adipose mesenchymal stromal cells response to ionizing radiation

Cytotherapy. 2016 Mar;18(3):384-401. doi: 10.1016/j.jcyt.2015.12.001. Epub 2016 Jan 15.

Authors

Osama Muhammad Maria¹, Slawomir Kumala², Mitra Heravi³, Alasdair Syme⁴, Nicoletta Eliopoulos⁵, Thierry Muanza⁶

Affiliations

¹ Experimental Medicine Department, Jewish General Hospital, Montreal, Canada; Surgery Department, Faculty of Medicine, Jewish General Hospital, Montreal, Canada; Radiation Oncology Department, Jewish General Hospital, Montreal, Canada.
² Radiation Oncology Department, Jewish General Hospital, Montreal, Canada; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Canada; Oncology Department, McGill University, Montreal, Canada.
³ Radiation Oncology Department, Jewish General Hospital, Montreal, Canada; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Canada; Human Genetics Department, McGill University, Montreal, Canada.
⁴ Radiation Oncology Department, Jewish General Hospital, Montreal, Canada; Oncology Department, McGill University, Montreal, Canada; Medical Physics Unit, Jewish General Hospital, Montreal, Canada.
⁵ Surgery Department, Faculty of Medicine, Jewish General Hospital, Montreal, Canada; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Canada.
⁶ Experimental Medicine Department, Jewish General Hospital, Montreal, Canada; Radiation Oncology Department, Jewish General Hospital, Montreal, Canada; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Canada; Oncology Department, McGill University, Montreal, Canada. Electronic address: tmuanza@yahoo.com.

PMID: 26780866
DOI: 10.1016/j.jcyt.2015.12.001

Abstract

Background aims: This study evaluates the biological response of adipose tissue-derived mesenchymal stromal cells (aMSCs) to ionizing radiation (IR).

Methods: Irradiated BALB/c mice aMSCs were characterized for functionality and phenotype. The clonogenic capacity of irradiated aMSCs was assessed and compared with those of metastatic breast cancer cell line (4T1) and normal mouse fibroblasts (NIH3T3-wt). We investigated the IR-induced DNA damage response, apoptosis, changes in cell cycle (CC) dynamics and protein and gene expression.

Results: Irradiated and non-irradiated aMSCs were able to differentiate into adipocytes, chondrocytes and osteocytes with no significant difference. Irradiated aMSCs maintained the expression of mesenchymal stromal cells (MSCs) surface antigens and, as expected, were negative for hematopoietic stem cells (HSCs) surface antigens when tested up to 7 days after IR for all irradiation doses with no significant difference. Clonogenically, irradiated aMSCs had higher relative survival fraction and plating efficiency than 4T1 and NIH3T3-wt. Irradiated aMSCs expressed higher □H2AX and significantly showed faster and more time-efficient IR-induced DNA damage response evident by up-regulated DNA-PKcs and RAD51. Two hours after IR, most of aMSCs DNA damage/repair-related genes showed up-regulation that disappeared within 6 h after IR. Irradiated aMSCs showed a significant rise and an earlier peak of p-ATM-dependent and -independent (p84/5E10-mediated) G2/M CC arrest compared with 4T1 and NIH3T3-wt.

Conclusions: After IR exposure, aMSCs showed a robust and time-efficient radiation-induced DNA damage repair response, stable phenotypical characteristics and multi-lineage differentiation potential, suggesting they may be reliable candidates for cell therapy in radiation oncology regenerative medicine.

Keywords: DNA damage repair; G2/M arrest; adipose; cell cycle; gene expression; ionizing radiation; mesenchymal stromal cells; radiation resistance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes / physiology
Adipocytes / radiation effects
Adipose Tissue / cytology*
Adipose Tissue / radiation effects
Animals
Cell Cycle / radiation effects
Cell Differentiation / physiology
Cell Differentiation / radiation effects
Cells, Cultured
Chondrocytes / physiology
Chondrocytes / radiation effects
Female
Mesenchymal Stem Cells / cytology*
Mesenchymal Stem Cells / radiation effects*
Mice
Mice, Inbred BALB C
NIH 3T3 Cells
Radiation, Ionizing*
Up-Regulation / radiation effects