Production of human entorhinal stellate cell-like cells by forward programming shows an important role of Foxp1 in reprogramming

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  • Tobias Bergmann
  • Yong Liu
  • Jonathan Skov
  • Leo Mogus
  • Julie Lee
  • Ulrich Pfisterer
  • Louis Francois Handfield
  • Andrea Asenjo-Martinez
  • Jimmy Tsz Hang Lee
  • Nikolaos Patikas
  • Mark Denham
  • Poul Hyttel
  • Menno P. Witter
  • Martin Hemberg

Stellate cells are principal neurons in the entorhinal cortex that contribute to spatial processing. They also play a role in the context of Alzheimer’s disease as they accumulate Amyloid beta early in the disease. Producing human stellate cells from pluripotent stem cells would allow researchers to study early mechanisms of Alzheimer’s disease, however, no protocols currently exist for producing such cells. In order to develop novel stem cell protocols, we characterize at high resolution the development of the porcine medial entorhinal cortex by tracing neuronal and glial subtypes from mid-gestation to the adult brain to identify the transcriptomic profile of progenitor and adult stellate cells. Importantly, we could confirm the robustness of our data by extracting developmental factors from the identified intermediate stellate cell cluster and implemented these factors to generate putative intermediate stellate cells from human induced pluripotent stem cells. Six transcription factors identified from the stellate cell cluster including RUNX1T1, SOX5, FOXP1, MEF2C, TCF4, EYA2 were overexpressed using a forward programming approach to produce neurons expressing a unique combination of RELN, SATB2, LEF1 and BCL11B observed in stellate cells. Further analyses of the individual transcription factors led to the discovery that FOXP1 is critical in the reprogramming process and omission of RUNX1T1 and EYA2 enhances neuron conversion. Our findings contribute not only to the profiling of cell types within the developing and adult brain’s medial entorhinal cortex but also provides proof-of-concept for using scRNAseq data to produce entorhinal intermediate stellate cells from human pluripotent stem cells in-vitro.

OriginalsprogEngelsk
Artikelnummer976549
TidsskriftFrontiers in Cell and Developmental Biology
Vol/bind10
ISSN2296-634X
DOI
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
The project was financed by The Independent Research Fund, Denmark under the grant (ID: DFF–7017-00071 and 8021-00048B), Lundbeck foundation (R296-2018-2287) and The Innovation Foundation [Brainstem (4108-00008B)]. KK acknowledges the Novo Nordisk Hallas-Møller Investigator grant (NNF16OC0019920). TP acknowledges the Novo Nordisk Foundation (Grant number NNF18CC0034900) and the Lundbeck Foundation (Grant number R190-2014-3904). MH and NP were supported by a core grant to the Wellcome Sanger Institute from the Wellcome Trust. L-FH was supported by Open Targets (OTAR038) and JL was supported by a CZI [2018-183503 (5022)] from the Chan Zuckerberg Initiative. MD acknowledges Lundbeck foundation (DANDRITE-R248-2016-2518).

Publisher Copyright:
Copyright © 2022 Bergmann, Liu, Skov, Mogus, Lee, Pfisterer, Handfield, Asenjo-Martinez, Lisa-Vargas, Seemann, Lee, Patikas, Kornum, Denham, Hyttel, Witter, Gorodkin, Pers, Hemberg, Khodosevich and Hall.

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