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

• Published in: Frontiers in cell and developmental biology Vol. 10; p. 976549
• Main Authors: Bergmann, Tobias, Liu, Yong, Skov, Jonathan, Mogus, Leo, Lee, Julie, Pfisterer, Ulrich, Handfield, Louis-Francois, Asenjo-Martinez, Andrea, Lisa-Vargas, Irene, Seemann, Stefan E, Lee, Jimmy Tsz Hang, Patikas, Nikolaos, Kornum, Birgitte Rahbek, Denham, Mark, Hyttel, Poul, Witter, Menno P, Gorodkin, Jan, Pers, Tune H, Hemberg, Martin, Khodosevich, Konstantin, Hall, Vanessa Jane
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 15-08-2022
• Subjects: Cell and Developmental Biology; forward programming; FOXP1; induced pluripotent stem cells; medial entorhinal cortex; stellate cells; stellate cells; induced pluripotent stem cells; medial entorhinal cortex; forward programming; FOXP1
• ISSN: 2296-634X; 2296-634X
• DOI: 10.3389/fcell.2022.976549

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
,
,
,
,
,
were overexpressed using a forward programming approach to produce neurons expressing a unique combination of
,
,
and BCL11B observed in stellate cells. Further analyses of the individual transcription factors led to the discovery that
is critical in the reprogramming process and omission of
and
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
.