Hematopoietic Stem Cell Regeneration Enhanced by Ectopic Expression of ROS-detoxifying Enzymes in Transplant Mice

Abstract

High levels of reactive oxygen species (ROS) can exhaust hematopoietic stem cells (HSCs). Thus, maintaining a low state of redox in HSCs by modulating ROS-detoxifying enzymes may augment the regeneration potential of HSCs. Our results show that basal expression of manganese superoxide dismutase (MnSOD) and catalase were at low levels in long-term and short-term repopulating HSCs, and administration of a MnSOD plasmid and lipofectin complex (MnSOD-PL) conferred radiation protection on irradiated recipient mice. To assess the intrinsic role of elevated MnSOD or catalase in HSCs and hematopoietic progenitor cells, the MnSOD or catalase gene was overexpressed in mouse hematopoietic cells via retroviral transduction. The impact of MnSOD and catalase on hematopoietic progenitor cells was mild, as measured by colony-forming units (CFUs). However, overexpressed catalase had a significant beneficial effect on long-term engraftment of transplanted HSCs, and this effect was further enhanced after an insult of low-dose γ-irradiation in the transplant mice. In contrast, overexpressed MnSOD exhibited an insignificant effect on long-term engraftment of transplanted HSCs, but had a significant beneficial effect after an insult of sublethal irradiation. Taken together, these results demonstrate that HSC function can be enhanced by ectopic expression of ROS-detoxifying enzymes, especially after radiation exposure in vivo.

Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner

“…9,30 In addition, ectopic expression of manganese superoxide dismutase and catalase in HSCs reduces IR-induced HSC injury. 39 However, the molecular mechanisms by which ROS mediates the induction of HSC senescence by IR were unknown. The results from our current study suggest that ROS may mediate IR-induced HSC senescence in a telomere-independent manner, because increased production of ROS by irradiated HSCs was not associated with telomere shortening in HSCs and their progeny, even though increased For personal use only.…”

Antioxidant N-acetyl-l-cysteine increases engraftment of human hematopoietic stem cells in immune-deficient mice

“…[2][3][4] In our study, we observed that NOD/SCID mice have significantly higher levels of reactive oxygen species (ROS) in bone marrow (BM) cells than other commonly used mouse strains. Given the previous studies from our laboratory 5,6 and others [7][8][9] showing that excessive ROS impaired the function of HSCs and that antioxidants were able to overcome the exhaustion of mouse HSCs in transplant recipients, we hypothesized that poor engraftment of HSCs in NOD/SCID mice could be partially attributed to higher levels of ROS in NOD/SCID BM. We used the antioxidant N-acetyl-Lcysteine (NAC) to reduce ROS levels in the NOD/SCID BM and demonstrated significant enhancement of the human cell engraftment.…”

Catalase Inhibits Ionizing Radiation-Induced Apoptosis in Hematopoietic Stem and Progenitor Cells

“…It has been shown that ectopic overexpression of CAT can protect a variety of tissues against oxidative stress-induced damage in animal models [19][20][21]. Furthermore, there is evidence indicating that CAT treatment may preserve hematopoietic stem cell (HSC) selfrenewal in long-term BM cultures [22].…”