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Granulosa Cells – The Key to Generating Functional Oocytes In Vitro?

Review of “Functional Oocytes Derived from Granulosa Cells” from Cell Reports by Stuart P. Atkinson

The guided differentiation of germline competent pluripotent stem cells reprogrammed from female somatic cells represents an exciting means to generate patient-specific oocytes and preserve/restore fertility [1, 2]. In the hope of accelerating this field of research, a team led by Lin Liu (Nankai University, Tianjin, China) recently explored the chemical reprogramming of granulosa cells – somatic cells that closely associated with oocyte, display amenability to reprogramming [3], and have been employed to successfully clone animals [4]  – as a safe and efficient strategy for the in vitro production of oocytes.

Writing in a recent Cell Reports article, Tian et al. now report that chemically-induced pluripotent stem cells (CiPSCs) generated from granulosa cells consistently differentiate into primordial-germ-cell-like cells and form functional genomically-stable oocytes that produce fertile mice [5].

Initial transcriptional analysis revealed that granulosa cells isolated from adult mouse ovaries displayed a profile similar to extra-embryonic endoderm-like cells, representing an intermediate stage toward CiPSCs when compared to fibroblasts. Tian et al. then attempted to reprogram granulosa cells via a chemical reprogramming approach developed initially for fibroblasts [6]; however, efficient reprogramming additionally required Rock inhibitor treatment, to improve attachment and proliferation and inhibit apoptosis of GCs, and crotonic acid treatment, to activate 2-cell embryo genes such as Zscan4. Interestingly, CiPSCs generated by this manner displayed longer telomeres and high genomic stability, as observed for PGCs in vivo, suggesting both the safety and effectiveness of the reprogramming process. CiPSCs from granulosa cells also exhibited an embryonic stem cell-like exhibited pluripotency and differentiation potential, as well as X-chromosome activation. Finally, and most encouragingly, the authors also found that CiPSCs could be readily differentiated into epiblast-like cells and then into primordial-germ-cell-like cells with the ability to form functional oocytes; furthermore, these oocytes possessed the ability to produce fertile mice, suggesting high germline competency of the original CiPSCs. 

The authors note that human fertility clinics discard granulosa cells as by-products of the oocyte retrieval process; can we now transfer this novel chemical reprogramming process from mouse to human granulosa cells as a means to treat infertility? 

For the answers to this question and for more on the in vitro generation of functional oocytes, stay tuned to the Stem Cells Portal!


  1. Hayashi K, Ogushi S, Kurimoto K, et al., Offspring from Oocytes Derived from in Vitro Primordial Germ Cell–like Cells in Mice. Science 2012;338:971.
  2. Gell JJ and Clark AT, Restoring Fertility with Human Induced Pluripotent Stem Cells: Are We There Yet? Cell Stem Cell 2018;23:777-779.
  3. Mao J, Zhang Q, Ye X, et al., Efficient Induction of Pluripotent Stem Cells from Granulosa Cells by Oct4 and Sox2. Stem Cells and Development 2013;23:779-789.
  4. Wakayama T, Perry ACF, Zuccotti M, et al., Full-term development of mice from enucleated oocytes injected with cumulus cell nuclei. Nature 1998;394:369-374.
  5. Tian C, Liu L, Ye X, et al., Functional Oocytes Derived from Granulosa Cells. Cell Reports 2019;29:4256-4267.e9.
  6. Zhao Y, Zhao T, Guan J, et al., A XEN-like State Bridges Somatic Cells to Pluripotency during Chemical Reprogramming. Cell 2015;163:1678-1691.