Capturing limbal epithelial stem cell population dynamics, signature and their niche [article]

Anna Altshuler, Aya Amitai Lange, Noam Tarazi, Sunanda Dey, Lior Strinkovsky, Swarnabh Bhattacharya, Shira Hadad-Porat, Waseem Nasser, Jusuf Imeri, Gil Ben-David, Beatrice Tiosano, Eran Berkowitz (+3 others)
2020 bioRxiv   pre-print
Stem cells (SCs) are traditionally viewed as rare, slow-cycling cells that follow deterministic rules dictating their self-renewal or differentiation. It was several decades ago, when limbal epithelial SCs (LSCs) that regenerate the corneal epithelium were one of the first sporadic, quiescent SCs ever discovered. However, LSC dynamics, heterogeneity and genetic signature are largely unknown. Moreover, recent accumulating evidence strongly suggested that epithelial SCs are actually abundant,
more » ... ually abundant, frequently dividing cells that display stochastic behavior. In this work, we performed an in-depth analysis of the murine limbal epithelium by single-cell RNA sequencing and quantitative lineage tracing. The generated data provided an atlas of cell states of the corneal epithelial lineage, and particularly, revealed the co-existence of two novel LSC populations that reside in separate and well defined sub-compartments. In the outer limbus, we identified a primitive widespread population of quiescent LSCs (qLSCs) that uniformly express Krt15/Gpha2/Ifitm3/Cd63 proteins, while the inner limbus host prevalent active LSCs (aLSCs) co-expressing Krt15-GFP/Atf3/Mt1-2/Socs3. Analysis of LSC population dynamics suggests that while qLSCs and aLSCs possess different proliferation rates, they both follow stochastic rules that dictate their self-renewal and differentiation. Finally, T cells were distributed at close proximity to qLSCs. Indeed, their absence or inhibition resulted with loss of quiescence and delayed wound healing. Taken together, we propose that divergent regenerative strategies are tailored to properly support tissue specific physiological constraints. The present study suggests that in the case of the cornea, quiescent epithelial SCs are abundant, follow stochastic rules and neutral drift dynamics.
doi:10.1101/2020.06.30.179754 fatcat:pwzspdyxkzedxhpz5eayzsz6ae