Abstract 4040: Age-related effects following exposure of bone marrow-derived mesenchymal stem cells to etoposide .

Abstract

Mesenchymal stem cells (MSCs) have been shown to be one of the populations that support hematopoietic stem cell (HSC) development within the bone marrow microenvironment. High dose myelosuppressive or ablative chemotherapy regimens that are utilized prior to bone marrow transplantation have the potential to damage MSCs, consistent with damage which we have previously reported for more differentiated stromal and osteoblast cells. As with more differentiated progenitor cells, interactions between MSCs and HSCs are vital to hematopoietic homeostasis with alterations of these interactions having the potential to hamper hematopoietic reconstitution following treatment. In the current study we begin to investigate age associated differences in the vulnerability of the microenvironment to stress utilizing primary human MSCs from passages 6 to 10, characterized functionally by adipocytic and osteogenic differentiation and surface expression profiling (CD105⁺CD44⁺CD166⁺CD45⁻). We have shown that treatment of MSCs with 25μM etoposide for 24 hours in-vitro causes the occurrence of dsDNA breaks that recover within 48 hours following treatment. In addition, chemotherapy induced stress was followed by an induction of p21. Homologous recombination associated transcripts (XRCC2, XRCC3, Rad51) were reduced following etoposide treatment relative to non-homologous end joining associated transcripts (Ku70, Ku80, DNA-PK), and the magnitude of these differences was augmented with age in-vitro. Pro-apoptotic transcripts Puma and Noxa and the anti-apoptosis associated Bcl-XL showed induction with treatment while Bcl-2 decreased, suggesting the wide range of genes that are responsive to chemotherapy exposure. These results provide insight into the damage responses of MSCs to etoposide and how DNA repair capabilities following chemotherapy could be influenced by patient age. A more mechanistic understanding of the recovery pathways that are altered with age may be valuable for innovative approaches to the treatment of elderly patients for whom escalated chemotherapy is required in an effort to optimize microenvironment supported immune system recovery.

Citation Format: Ian Hare, Marieta Gencheva, Laura Gibson. Age-related effects following exposure of bone marrow-derived mesenchymal stem cells to etoposide . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4040. doi:10.1158/1538-7445.AM2013-4040