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Directed differentiation of human iPSCs to functional ovarian granulosa-like cells via transcription factor overexpression.

Publication ,  Journal Article
Pierson Smela, MD; Kramme, CC; Fortuna, PRJ; Adams, JL; Su, R; Dong, E; Kobayashi, M; Brixi, G; Kavirayuni, VS; Tysinger, E; Kohman, RE ...
Published in: eLife
February 2023

An in vitro model of human ovarian follicles would greatly benefit the study of female reproduction. Ovarian development requires the combination of germ cells and several types of somatic cells. Among these, granulosa cells play a key role in follicle formation and support for oogenesis. Whereas efficient protocols exist for generating human primordial germ cell-like cells (hPGCLCs) from human induced pluripotent stem cells (hiPSCs), a method of generating granulosa cells has been elusive. Here, we report that simultaneous overexpression of two transcription factors (TFs) can direct the differentiation of hiPSCs to granulosa-like cells. We elucidate the regulatory effects of several granulosa-related TFs and establish that overexpression of NR5A1 and either RUNX1 or RUNX2 is sufficient to generate granulosa-like cells. Our granulosa-like cells have transcriptomes similar to human fetal ovarian cells and recapitulate key ovarian phenotypes including follicle formation and steroidogenesis. When aggregated with hPGCLCs, our cells form ovary-like organoids (ovaroids) and support hPGCLC development from the premigratory to the gonadal stage as measured by induction of DAZL expression. This model system will provide unique opportunities for studying human ovarian biology and may enable the development of therapies for female reproductive health.

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Published In

eLife

DOI

EISSN

2050-084X

ISSN

2050-084X

Publication Date

February 2023

Volume

12

Start / End Page

e83291

Related Subject Headings

  • Transcription Factors
  • Ovary
  • Oogenesis
  • Induced Pluripotent Stem Cells
  • Humans
  • Female
  • Cell Differentiation
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
  • 31 Biological sciences
 

Citation

APA
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Pierson Smela, M. D., Kramme, C. C., Fortuna, P. R. J., Adams, J. L., Su, R., Dong, E., … Church, G. M. (2023). Directed differentiation of human iPSCs to functional ovarian granulosa-like cells via transcription factor overexpression. ELife, 12, e83291. https://doi.org/10.7554/elife.83291
Pierson Smela, Merrick D., Christian C. Kramme, Patrick R. J. Fortuna, Jessica L. Adams, Rui Su, Edward Dong, Mutsumi Kobayashi, et al. “Directed differentiation of human iPSCs to functional ovarian granulosa-like cells via transcription factor overexpression.ELife 12 (February 2023): e83291. https://doi.org/10.7554/elife.83291.
Pierson Smela MD, Kramme CC, Fortuna PRJ, Adams JL, Su R, Dong E, et al. Directed differentiation of human iPSCs to functional ovarian granulosa-like cells via transcription factor overexpression. eLife. 2023 Feb;12:e83291.
Pierson Smela, Merrick D., et al. “Directed differentiation of human iPSCs to functional ovarian granulosa-like cells via transcription factor overexpression.ELife, vol. 12, Feb. 2023, p. e83291. Epmc, doi:10.7554/elife.83291.
Pierson Smela MD, Kramme CC, Fortuna PRJ, Adams JL, Su R, Dong E, Kobayashi M, Brixi G, Kavirayuni VS, Tysinger E, Kohman RE, Shioda T, Chatterjee P, Church GM. Directed differentiation of human iPSCs to functional ovarian granulosa-like cells via transcription factor overexpression. eLife. 2023 Feb;12:e83291.

Published In

eLife

DOI

EISSN

2050-084X

ISSN

2050-084X

Publication Date

February 2023

Volume

12

Start / End Page

e83291

Related Subject Headings

  • Transcription Factors
  • Ovary
  • Oogenesis
  • Induced Pluripotent Stem Cells
  • Humans
  • Female
  • Cell Differentiation
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
  • 31 Biological sciences