Talk of RA synthesis in the skin after deep wounding:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594970/
While important advancements have been made on the role of Wnt1/Shh5 signaling, γ-δ T cells6, and myofibroblasts7, the mechanisms by which epidermal stem cells induce skin regeneration are still unclear3.
Recent evidence has shown that antiviral pathways are hallmarks of diverse stem cells8.
Additionally, we reported that damaged skin activates Toll Like Receptor 3 (TLR3) signaling to induce hair follicle regeneration9. Together, these findings suggest that in addition to other pathways, TLR3 signaling as a damage sensor might connect stem cell activity to regeneration.
RA has broad uses in medicine, for example in the treatment of acute promyelocytic leukemia. However, in all contexts, treatment can result in poor efficacy and significant side effects.
This might partly be due to the artificial nature of exogenous RA delivery in these clinical settings; inducing
___endogenous synthesis__ might be far more effective, for example because of the simultaneous induction of chaperones.
In support of this, we find that in conditions where ALDH1A3 is maximally induced, such as with RA plus Poly (I:C) (Fig. 4a), stem cell gene induction (Supplementary Fig. 3) is also maximally induced—up to ~250 fold more than with ___exogenous___ RA treatment alone
. This implies that methods of inducing nuclear steroid hormone ligand production will be more efficacious than simple ligand addition in their respective clinical indications.
Altogether our results demonstrate that dsRNA/TLR3 stimulates preferential RA accumulation in a pattern that correlates with future hair follicle neogenesis, reminiscent of morphogen signaling
. Although there are differences between human facial rejuvenation and mouse WIHN, here we demonstrate how noncoding dsRNA activates TLR3 to trigger RA synthesis and signaling to promote regeneration.
Our work implies that therapeutic combination of TLR3 agonists with RA might synergistically enhance regeneration in humans.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594970/
While important advancements have been made on the role of Wnt1/Shh5 signaling, γ-δ T cells6, and myofibroblasts7, the mechanisms by which epidermal stem cells induce skin regeneration are still unclear3.
Recent evidence has shown that antiviral pathways are hallmarks of diverse stem cells8.
Additionally, we reported that damaged skin activates Toll Like Receptor 3 (TLR3) signaling to induce hair follicle regeneration9. Together, these findings suggest that in addition to other pathways, TLR3 signaling as a damage sensor might connect stem cell activity to regeneration.
RA has broad uses in medicine, for example in the treatment of acute promyelocytic leukemia. However, in all contexts, treatment can result in poor efficacy and significant side effects.
This might partly be due to the artificial nature of exogenous RA delivery in these clinical settings; inducing
___endogenous synthesis__ might be far more effective, for example because of the simultaneous induction of chaperones.
In support of this, we find that in conditions where ALDH1A3 is maximally induced, such as with RA plus Poly (I:C) (Fig. 4a), stem cell gene induction (Supplementary Fig. 3) is also maximally induced—up to ~250 fold more than with ___exogenous___ RA treatment alone
. This implies that methods of inducing nuclear steroid hormone ligand production will be more efficacious than simple ligand addition in their respective clinical indications.
Altogether our results demonstrate that dsRNA/TLR3 stimulates preferential RA accumulation in a pattern that correlates with future hair follicle neogenesis, reminiscent of morphogen signaling
. Although there are differences between human facial rejuvenation and mouse WIHN, here we demonstrate how noncoding dsRNA activates TLR3 to trigger RA synthesis and signaling to promote regeneration.
Our work implies that therapeutic combination of TLR3 agonists with RA might synergistically enhance regeneration in humans.