RT Journal Article
SR Electronic
T1 Capturing limbal epithelial stem cell population dynamics, signature, and their niche
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.30.179754
DO 10.1101/2020.06.30.179754
A1 Anna Altshuler
A1 Aya Amitai-Lange
A1 Noam Tarazi
A1 Sunanda Dey
A1 Lior Strinkovsky
A1 Swarnabh Bhattacharya
A1 Shira Hadad-Porat
A1 Waseem Nasser
A1 Jusuf Imeri
A1 Gil Ben-David
A1 Beatrice Tiosano
A1 Eran Berkowitz
A1 Nathan Karin
A1 Yonatan Savir
A1 Ruby Shalom-Feuerstein
YR 2020
UL http://biorxiv.org/content/early/2020/07/01/2020.06.30.179754.abstract
AB 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, 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 similar stochastic rules that dictate their self-renewal and differentiation. Finally, T cells were distributed in close proximity to qLSCs. Indeed, their absence or inhibition resulted in the 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.Competing Interest StatementThe authors have declared no competing interest.