Disruption of Cell-Adhesion Signaling Resolves Unwanted Progenitor Specification in Stem Cell-Derived α and β Cell...

Area of Science:

• Cell Biology
• Regenerative Medicine
• Endocrinology

Background:

• Stem cell-derived alpha (SC-α) cells are being developed for type 1 diabetes (T1D) therapy alongside stem cell-derived beta (SC-β) cells.
• SC-β cell differentiation protocols can yield off-target populations causing graft outgrowths, but SC-α cell outgrowth has not been studied.

Purpose of the Study:

• To investigate the potential for outgrowths from engrafted SC-α cells.
• To compare the mechanisms driving outgrowths in SC-α and SC-β cell grafts.
• To identify strategies for mitigating outgrowth formation in cell-based T1D therapies.

Main Methods:

• Engraftment of SC-α cells and analysis of resulting tissue.
• Single-cell RNA sequencing to characterize outgrowth-driving cell populations.
• Inhibition of signaling pathways (Notch) and cell-cell adhesion mechanisms.

Main Results:

• Engrafted SC-α cells form outgrowths with a similar composition to SC-β cell outgrowths.
• Shared outgrowth-driving populations in both SC-α and SC-β cells are marked by SOX9, CDX2, or SOX2.
• Cell-adhesion signaling is enriched in outgrowth-driving populations; disrupting this signaling reduces outgrowth propensity.

Conclusions:

• SC-α cells, like SC-β cells, can generate problematic outgrowths in T1D cell therapy grafts.
• Targeting cell-adhesion signaling and progenitor cell clusters is crucial for improving the safety of SC-α and SC-β cell therapies for T1D.