Peripheral Neuron-Organoid Interaction Induces Colonic Epithelial Differentiation via Non-Synaptic Substance P Secretion

Int J Stem Cells. 2023 Aug 30;16(3):269-280. doi: 10.15283/ijsc23026. Epub 2023 Jun 30.


Background and objectives: The colonic epithelial layer is a complex structure consisting of multiple cell types that regulate various aspects of colonic physiology, yet the mechanisms underlying epithelial cell differentiation during development remain unclear. Organoids have emerged as a promising model for investigating organogenesis, but achieving organ-like cell configurations within colonic organoids is challenging. Here, we investigated the biological significance of peripheral neurons in the formation of colonic organoids.

Methods and results: Colonic organoids were co-cultured with human embryonic stem cell (hESC)-derived peripheral neurons, resulting in the morphological maturation of columnar epithelial cells, as well as the presence of enterochromaffin cells. Substance P released from immature peripheral neurons played a critical role in the development of colonic epithelial cells. These findings highlight the vital role of inter-organ interactions in organoid development and provide insights into colonic epithelial cell differentiation mechanisms.

Conclusions: Our results suggest that the peripheral nervous system may have a significant role in the development of colonic epithelial cells, which could have important implications for future studies of organogenesis and disease modeling.

Keywords: Colonic organoid; Gut development; Inter-organ crosstalk; Organogenesis; Peripheral neuron; Pluripotent stem cell.

Grants and funding

Acknowledgments This study was supported by the National Research Foundation of Korea (NRF-2022M3A9H1016308, NRF-2022R1F1A1066611, NRF-2023R1A2C2007120), the Ministry of SMEs and startups (S3098634), the Korean Fund for Regenerative Medicine (2021M3E5E5096744), and the KIST Institutional Program (Project No.2Z05790-19-037).