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Deciphering the Role of Lef-1 in Lung Basal Cells

Review of “Lef-1 controls cell cycle progression in airway basal cells to regulate proliferation and differentiation” from STEM CELLS by Stuart P. Atkinson

Various stem cell populations in the lung coordinate tissue maintenance and repair [1, 2]; while Wnt signaling promotes stem cell expansion and the regeneration of injured tissue [3, 4] (See the STEM CELLSarticle here!), how this pathway impacts lung stem cell-mediated regeneration remains relatively unknown. Airway basal cells serve as the primary stem/progenitor cell population of the mouse trachea and human conducting surface airway epithelium of the cartilaginous airways [5]. Recent research has implicated the high mobility group (HMG) domain transcription factor Lef-1, an effector of the canonical Wnt pathway, as a crucial factor controlling airway basal cell self-renewal and/or lineage commitment [6, 7].

Researchers from the laboratory of John F. Engelhardt (University of Iowa, Iowa City, Iowa, USA) sought to understand the mechanisms that regulate when and how mouse basal cells proliferate, migrate, and differentiate with a focus on Lef-1. In their new STEM CELLS article [8], Jensen-Cody et al. now report the requirement of Lef-1 for proper airway basal cell function and highlight the possibility of modulating Lef-1 function to improve lung-based regenerative medicine.

Following the conditional deletion of Lef-1, basal cells stopped proliferating (although only transiently) and stalled at the G1/S phase of the cell cycle; furthermore, Lef-1 knockout basal cells failed to give rise to luminal tracheal cell types during long-term air-liquid interface in vitro culture or fully regenerate the injured tracheal epithelium in vivo, both suggestive of a loss of normal self-renewing capacity.

The authors profiled the transcriptome of basal cells after Lef-1 knockout to understand why, which revealed the significant downregulation of genes crucial to DNA damage responses and cell cycle progression, such as Checkpoint kinase 1 (Chk1), a serine/threonine-specific protein kinase encoded by the Chek1 gene. Interestingly, Lef-1 knockdown failed to increase the expression of DNA damage-associated markers; therefore, the authors hypothesized that Lef-1 promotes cell cycle progression during the late G1 phase before any significant DNA replication that may be associated with enhanced DNA repair requirements. Interestingly, the chemical inhibition of Chk1 affected basal cells in a comparable manner to Lef-1 knockout.

Overall, the authors believe that modulating Lef-1 expression in basal cells may improve their regenerative capacity and improve lung-based therapies for various diseases and disorders. Future research in this area may include the precise definition of Lef-1 targets, which could involve transcriptional and post-transcriptional mechanisms.

For more details on the role of Lef-1 in airway basal cells and the potential of this research to improve lung regeneration strategies, stay tuned to the Stem Cells Portal!

References

  1. Hogan Brigid LM, Barkauskas Christina E, Chapman Harold A, et al., Repair and Regeneration of the Respiratory System: Complexity, Plasticity, and Mechanisms of Lung Stem Cell Function. Cell Stem Cell 2014;15:123-138.
  2. Lynch TJ and Engelhardt JF, Progenitor Cells in Proximal Airway Epithelial Development and Regeneration. Journal of Cellular Biochemistry 2014;115:1637-1645.
  3. Zhang Y, Goss AM, Cohen ED, et al., A Gata6-Wnt pathway required for epithelial stem cell development and airway regeneration. Nature Genetics 2008;40:862-870.
  4. Lynch TJ, Anderson PJ, Xie W, et al., Wnt Signaling Regulates Airway Epithelial Stem Cells in Adult Murine Submucosal Glands. STEM CELLS 2016;34:2758-2771.
  5. Rock JR, Onaitis MW, Rawlins EL, et al., Basal cells as stem cells of the mouse trachea and human airway epithelium. Proceedings of the National Academy of Sciences 2009;106:12771.
  6. Lynch TJ, Anderson PJ, Rotti PG, et al., Submucosal Gland Myoepithelial Cells Are Reserve Stem Cells That Can Regenerate Mouse Tracheal Epithelium. Cell Stem Cell 2018;22:779.
  7. Tata A, Kobayashi Y, Chow RD, et al., Myoepithelial Cells of Submucosal Glands Can Function as Reserve Stem Cells to Regenerate Airways after Injury. Cell Stem Cell 2018;22:668-683.e6.
  8. Jensen-Cody CW, Crooke AK, Rotti PG, et al., Lef-1 controls cell cycle progression in airway basal cells to regulate proliferation and differentiation. STEM CELLS 2021;39:1221-1235.