Weddle, D. | bioRxiv Science

bioRxiv2022

The relationship between PD-L1 and quiescence in melanocyte stem cell aging.

A central aspect of life-long stem cell function in slow cycling stem cells is the proper regulation of cellular quiescence. How the quiescent state is achieved, whether all quiescent cells are equivalent, and if the quiescent stem cell pool changes with age are all questions that remain unanswered. Using quiescent melanocyte stem cells (qMcSC) as a model, we found that stem cell quiescence is neither a singular nor static process and can be heterogeneous. As one example of this heterogeneity, we show that a portion of qMcSCs expresses the immune checkpoint protein PD-L1 at the cell membrane (PD-L1mem+), PD-L1mem+ qMcSCs are better retained with age, and that the aged quiescent McSC pool is transcriptomically more deeply quiescent. Collectively these findings demonstrate that PD-L1 expression is a physiological attribute of quiescence in McSCs and PD-L1mem+ quiescent stem cells may be good targets for reactivation in the context of aging.

cell biology↗

bioRxiv2022

Robust and durable prophylactic protection conferred by RNA interference in preclinical models of SARS-CoV-2

RNA interference is a natural antiviral mechanism that could be harnessed to combat SARS-CoV-2 infection by targeting and destroying the viral genome. We screened lipophilic small-interfering RNA (siRNA) conjugates targeting highly conserved regions of the SARS-CoV-2 genome and identified leads targeting outside of the spike-encoding region capable of achieving [≥]3-log viral reduction. Serial passaging studies demonstrated that a two-siRNA combination prevented development of resistance compared to a single-siRNA approach. A two-siRNA combination delivered intranasally protected Syrian hamsters from weight loss and lung pathology by viral infection upon prophylactic administration but not following onset of infection. Together, the data support potential utility of RNAi as a prophylactic approach to limit SARS-CoV-2 infection that may help combat emergent variants, complement existing interventions, or protect populations where vaccines are less effective. Most importantly, this strategy has implications for developing medicines that may be valuable in protecting against future coronavirus pandemics.

pharmacology and toxicology↗