p38 MAPK as a gatekeeper of reprogramming in mouse migratory primordial germ cells

Daiji Okamura; Aoi Kohara; Yuta Chigi; Tomoka Katayama; Jafar Sharif; Jun Wu; Yumi Ito-Matsuoka; Yasuhisa Matsui

doi:10.3389/fcell.2024.1410177

p38 MAPK as a gatekeeper of reprogramming in mouse migratory primordial germ cells

Front Cell Dev Biol. 2024 Jun 6:12:1410177. doi: 10.3389/fcell.2024.1410177. eCollection 2024.

Authors

Daiji Okamura^#¹, Aoi Kohara^#¹, Yuta Chigi^#², Tomoka Katayama¹, Jafar Sharif³, Jun Wu^{4

5}, Yumi Ito-Matsuoka⁶, Yasuhisa Matsui^{6

7

8}

Affiliations

¹ Department of Advanced Bioscience, Faculty of Agriculture, Kindai University, Nara, Japan.
² Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.
³ Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan.
⁴ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, United States.
⁵ Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States.
⁶ Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
⁷ Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
⁸ Graduate School of Medicine, Tohoku University, Sendai, Japan.

^# Contributed equally.

Abstract

Mammalian germ cells are derived from primordial germ cells (PGCs) and ensure species continuity through generations. Unlike irreversible committed mature germ cells, migratory PGCs exhibit a latent pluripotency characterized by the ability to derive embryonic germ cells (EGCs) and form teratoma. Here, we show that inhibition of p38 mitogen-activated protein kinase (MAPK) by chemical compounds in mouse migratory PGCs enables derivation of chemically induced Embryonic Germ-like Cells (cEGLCs) that do not require conventional growth factors like LIF and FGF2/Activin-A, and possess unique naïve pluripotent-like characteristics with epiblast features and chimera formation potential. Furthermore, cEGLCs are regulated by a unique PI3K-Akt signaling pathway, distinct from conventional naïve pluripotent stem cells described previously. Consistent with this notion, we show by performing ex vivo analysis that inhibition of p38 MAPK in organ culture supports the survival and proliferation of PGCs and also potentially reprograms PGCs to acquire indefinite proliferative capabilities, marking these cells as putative teratoma-producing cells. These findings highlight the utility of our ex vivo model in mimicking in vivo teratoma formation, thereby providing valuable insights into the cellular mechanisms underlying tumorigenesis. Taken together, our research underscores a key role of p38 MAPK in germ cell development, maintaining proper cell fate by preventing unscheduled pluripotency and teratoma formation with a balance between proliferation and differentiation.

Keywords: EGCs; gatekeeper; migratory primordial germ cells; p38 MAPK; pluripotency; reprogramming; teratoma.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from JSPS KAKENHI [Grant Number JP20K06661, Grant-in-Aid for Scientific Research (C) to DO, Grant Number JP23K05788, Grant-in-Aid for Scientific Research (C) to YM], Kindai University Research Enhancement Grant (IP003, KD2004, KD2101), the Ito Foundation, and the Urakami Foundation for Food and Food Culture Promotion, and partly supported by the Cooperative Research Project Program of Joint Usage/Research Center at the Institute of Development, Aging and Cancer, Tohoku University.