TGFbeta superfamily signaling regulates the state of human stem cell pluripotency and capacity to create well-structured telencephalic organoids.

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Publication Year:
2022
Authors:
Momoko Watanabe, Jessie E Buth, Jillian R Haney, Neda Vishlaghi, Felix Turcios, Lubayna S Elahi, Wen Gu, Caroline A Pearson, Arinnae Kurdian, Natella V Baliaouri, Amanda J Collier, Osvaldo A Miranda, Natassia Dunn, Di Chen, Shan Sabri, Luis de la Torre-Ubieta, Amander T Clark, Kathrin Plath, Heather R Christofk, Harley I Kornblum, Michael J Gandal, Bennett G Novitch
PubMed ID:
36179695
Funding Grants:
Public Summary:
Brain organoids generated from human pluripotent stem cells (hPSCs) are a promising system for studying the distinct features of the developing human brain and the underlying causes of many neurological disorders. While organoid technology is steadily advancing, many challenges remain, including potential batch-to-batch and cell-line-to-cell-line variability, and structural inconsistency. Here, we demonstrate that a major contributor to cortical organoid quality is the way hPSCs are maintained prior to differentiation. Optimal results were achieved using particular fibroblast-feeder-supported hPSCs rather than feeder-independent cells, differences that were reflected in their transcriptomic states at the outset. Feeder-supported hPSCs displayed activation of diverse transforming growth factor beta (TGFbeta) superfamily signaling pathways and increased expression of genes connected to naive pluripotency. We further identified combinations of TGFbeta-related growth factors that are necessary and together sufficient to impart broad telencephalic organoid competency to feeder-free hPSCs and enhance the formation of well-structured brain tissues suitable for disease modeling.
Scientific Abstract:
Telencephalic organoids generated from human pluripotent stem cells (hPSCs) are a promising system for studying the distinct features of the developing human brain and the underlying causes of many neurological disorders. While organoid technology is steadily advancing, many challenges remain, including potential batch-to-batch and cell-line-to-cell-line variability, and structural inconsistency. Here, we demonstrate that a major contributor to cortical organoid quality is the way hPSCs are maintained prior to differentiation. Optimal results were achieved using particular fibroblast-feeder-supported hPSCs rather than feeder-independent cells, differences that were reflected in their transcriptomic states at the outset. Feeder-supported hPSCs displayed activation of diverse transforming growth factor beta (TGFbeta) superfamily signaling pathways and increased expression of genes connected to naive pluripotency. We further identified combinations of TGFbeta-related growth factors that are necessary and together sufficient to impart broad telencephalic organoid competency to feeder-free hPSCs and enhance the formation of well-structured brain tissues suitable for disease modeling.