Stem Cell Engineering Reveals New Clues to Rebuilding Beta Cells

Loss of β-cell identity and dedifferentiation toward an α cell–like state are increasingly recognized as contributors to β-cell dysfunction in type 2 diabetes (T2D), but new findings suggest that one gene implicated in that process, secreted modular calcium-binding protein 1 (SMOC1), may also play a distinct physiological role earlier in human β-cell development.¹

“In the previous study, there were many, several reports that SMOC1 is a developmentally important gene,” said Jun Park, PhD, staff scientist, City of Hope, in an interview with The American Journal of Managed Care (AJMC). “However, there was no study yet on its importance in the pancreas. So, we thought that maybe SMOC1 is one gene candidate that is important in pancreatic development.”

SMOC1 is a basement membrane protein known to modulate growth factor signaling and influence cell differentiation, with established roles in ocular and limb development. In adult human islets affected by T2D, altered SMOC1 expression has been associated with reduced insulin expression and molecular features of β-cell dysfunction.² Whether SMOC1 also contributes to normal endocrine cell development and maturation had not previously been established.

Modeling Development With Stem Cell–Derived Islets

Researchers used the H1 human pluripotent stem cell line (WiCell) differentiated into stem cell–derived islet-like clusters (SC-islets) using a previously published protocol to investigate SMOC1’s role during β-cell development.^{1, 3} CRISPR/Cas9 genome editing was used to generate SMOC1 knockout (KO) and inducible knock-in (KI) SC-islet lines, allowing investigators to evaluate endocrine cell identity, cell numbers, and maturation using immunostaining and functional assays.

SMOC1 expression was regulated throughout differentiation, a pattern consistent with a developmental role distinct from its previously described association with β-cell dysfunction in adult T2D islets.¹

NKX6.1 Loss Without Disrupted Early Lineage Specification

SMOC1 KO SC-islets showed a marked, selective reduction in expression of NKX6.1, a transcription factor essential for maintaining β-cell identity, whereas expression of PDX1 and NGN3 remained unchanged. This pattern is consistent with impaired stabilization of β-cell identity rather than defective early endocrine lineage specification.

Overall SC-islet size and gross morphology were similar between control and SMOC1 KO cultures, but the proportion of NKX6.1-positive β cells was significantly reduced in the knockout lines. Restoration of SMOC1 expression using the inducible KI model restored NKX6.1-positive β-cell identity and improved features associated with β-cell maturation.

“We hope that we find further clues from those functional analyses, and we hope we can get much more mature β cells and enhance the lifespan of the transplanted model,” said Park.

A Developmental Regulator Distinct From Its Role in T2D

Taken together, the findings suggest that SMOC1 functions as a physiological stabilizer of β-cell identity during development, with a role that appears distinct from its previously described association with β-cell dedifferentiation in adult T2D islets.²

The authors note that SC-islet models provide a scalable and genetically tractable human platform for identifying additional stage-specific regulators of endocrine cell development that could inform future studies of diabetes pathogenesis and β-cell replacement strategies.¹

For payers and health systems monitoring advances in diabetes cell therapy, these findings highlight that stem cell–derived islet products remain in an early discovery phase focused on improving the purity, stability, and durability of insulin-producing cells before transplantation. Identifying genes such as SMOC1 that help maintain β-cell identity may eventually improve manufacturing consistency and long-term graft performance for future cell-based therapies. However, translating findings from CRISPR-edited SC-islet models into clinically deployable therapies will require substantial additional preclinical and clinical development, and these results do not support any near-term changes to clinical practice, coverage decisions, or care pathways.

References

1. Park J, Lee J, Aldaco J, et al. Deletion of SMOC1 impairs endocrine cell fate acquisition in human stem cell-derived pancreatic islets. Diabetes. https://doi.org/10.2337/db26-2675-P
2. Kang, RB, Varela M, Oh E, et al. Human pancreatic α-cell heterogeneity and trajectory inference analyses reveal SMOC1 as a β-cell dedifferentiation gene. Nat Commun. https://doi.org/10.1038/s41467-025-62670-5
3. Hogrebe NJ, Maxwell KG, Augsornworawat P, et al. Generation of insulin-producing pancreatic β cells from multiple human stem cell lines. Nat Protoc. 2021;16(9):4109-4143. doi: 10.1038/s41596-021-00560-y