Organ injury accelerates stem cell differentiation by modulating a fate-transducing lateral inhibition circuit

Sanders, E. N.; Sun, H.-T.; Tabatabaee, S.; Lang, C. F.; van Dijk, S. G.; Su, Y.-H.; Labott, A.; Idris, J.; Marchetti, M.; Xie, S.; O'Brien, L. E.

doi:10.1101/2024.12.29.630675

bioRxiv · 10.1101/2024.12.29.630675

Organ injury accelerates stem cell differentiation by modulating a fate-transducing lateral inhibition circuit

Sanders, E. N.·Sun, H.-T.·Tabatabaee, S.·Lang, C. F.·van Dijk, S. G.·Su, Y.-H.·Labott, A.·Idris, J.·Marchetti, M.·Xie, S.·O'Brien, L. E.

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Abstract

To rebuild tissue form and function, injured organs accelerate the differentiation of replacement stem cell progeny. Here we demonstrate that injury-induced factors open the throttle on faster differentiation by streamlining the archetypal signaling circuit that patterns cell fates. During normal turnover of the adult Drosophila intestine, fates are patterned by a conserved lateral inhibition circuit: In stem cell pairs, mutual activation of Notch receptor by Delta ligand feeds back to create opposing states of high Notch/low Delta and low Notch/high Delta; cells terminally differentiate once their Notch activity exceeds a fate-deciding threshold. After feeding flies a gut-damaging toxin, we perform in vivo imaging of real-time intestinal repair and trace Notch reporter dynamics in single cells. We find that tissue damage causes the speed of Notch signal activation to accelerate dramatically; faster activation expedites terminal differentiation by propelling cells past the critical Notch threshold more quickly. Combining single-cell analyses with dynamical modeling, we show that faster activation results from aberrant elevation of Delta ligand due to loss of time-delaying circuit feedback. Injury abolishes feedback via a cytokine-JAK-STAT relay from damaged cells to stem cells, causing stem cells to deactivate the Notch co-repressor that normally turns off Delta. Thus, organ injury unmasks latent plasticity in Notch-Delta lateral inhibition to propel the differentiation of new replacement cells. By unifying temporal and spatial fate control in a single, adaptable signaling circuit, organs tune stem cell dynamics to meet environmental challenges.

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Sanders, E. N., Sun, H.-T., Tabatabaee, S., Lang, C. F., van Dijk, S. G., Su, Y.-H., Labott, A., Idris, J., Marchetti, M., Xie, S., O'Brien, L. E.. 2024-12-30. Organ injury accelerates stem cell differentiation by modulating a fate-transducing lateral inhibition circuit. https://doi.org/10.1101/2024.12.29.630675

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