Palma, L. | Search bioRxiv

bioRxiv2022

Adult Hox gene expression promotes periosteal stem cell maintenance and mediates reprogramming in a regionally restricted manner

Periosteal stem and progenitor cells are pivotal to the growth and lifelong turnover of bone and underpin its capacity to regenerate. Adjusting the potency of this cell population will therefore be critical to the successful generation and application of new bone repair therapies. Following their role in patterning the embryonic skeleton, Hox genes remain regionally expressed in mesenchymal stromal cell populations of the adult skeleton. Here we show that Hoxa10 is most expressed in the most uncommitted periosteal stem cell and that Hox maintains these skeletal stem cells in a multipotential, uncommitted state, thereby preventing their differentiation into bone. We demonstrate that Hoxa10 mediates the reprogramming of periosteal progenitors towards a stem cell state with greater self-renewal capacity and also establish that region-specific Hox genes mediate cell reprogramming in distinct anatomical regions, demonstrating the continued functional relevance of the embryonic Hox profile in adult stem cells. Together, our data describe a master regulator role of Hox in skeletal stem and progenitor cells and help provide insight into the development of cell-based therapies for treatment of at-risk bone fractures and other bone-related ailments.

molecular biology↗

bioRxiv2021

Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production

Glucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in GBM relative to other human cancers and found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers. Treatment of patient-derived GBM cells with the FDA-approved cysteine compound N-acetylcysteine (NAC) reduce GBM cell growth and mitochondrial oxygen consumption, which was worsened by glucose starvation. Mechanistic experiments revealed that cysteine compounds induce rapid mitochondrial H2O2 production and reductive stress in GBM cells, an effect blocked by oxidized glutathione, thioredoxin, and redox enzyme overexpression. These findings indicate that GBM is uniquely susceptible to NAC-driven reductive stress and could synergize with glucose-lowering treatments for GBM.

cancer biology↗