# Loss of ABCC6 in Human Mesenchymal Stem Cells Leads to Elevated Reactive Oxygen Species Formation and a Senescence-like Phenotype

## TL;DR

This study shows that losing the ABCC6 gene in human stem cells increases harmful oxygen molecules and causes aging-like changes, suggesting antioxidants might help treat the disease.

## Contribution

The study reveals a novel link between ABCC6 deficiency, oxidative stress, and a senescence-like phenotype in human mesenchymal stem cells.

## Key findings

- ABCC6 knockdown increases reactive oxygen species and oxidative damage in hMSCs.
- ABCC6 deficiency induces a p53-dependent senescence-like phenotype in human stem cells.
- Antioxidants like Trolox can reverse oxidative stress and senescence caused by ABCC6 loss.

## Abstract

Pseudoxanthoma elasticum (PXE) is an autosomal-recessive disorder caused by mutations in ATP-binding cassette subfamily C member 6 (ABCC6). In addition to the calcification and fragmentation of elastic fibers as the pathomechanistic cause of PXE, systemic and cellular oxidative stress have been reported. Human mesenchymal stem cells (hMSCs) with an ABCC6 knockdown were chosen to further investigate the oxidative stress associated with ABCC6 deficiency. The cells were treated with hydrogen peroxide to mimic external oxidative stress and the antioxidant Trolox to examine the cells’ reaction to decreased oxidative stress. The level of different types of reactive species (RS) like nitric oxide and reactive oxygen species, the senescent phenotype, oxidative damage and mRNA expression of oxidative stress-related genes were evaluated. Knockdown of ABCC6 was shown to increase RS levels in hMSCs, induce a p53-dependent senescence-like phenotype and increase oxidative damage, while the mRNA expression of oxidative defense genes was elevated. The ABCC6-deficient cells exhibited an altered reaction to additional oxidative stress and the incubation with Trolox reversed these changes induced by ABCC6 knockdown. Our findings provide further evidence linking ABCC6-deficiency to oxidative stress and a senescence-like phenotype, while pointing towards antioxidants as part of a potential treatment for PXE.