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2025

Commun Biol. 2025 Aug 29;8(1):1302. doi: 10.1038/s42003-025-08763-9.

Stress-inducible phosphoprotein 1 (STIP1) is a critical stemness regulator in mouse embryonic stem cells and early mammalian development

Camila Felix de Lima Fernandes, Marilene Hohmuth Lopes, Maria Clara da Silva Souza, Samuel Ribeiro Soares, Jenny Andrea Arévalo-Romero, Rachel E Lackie, Bárbara Paranhos Coelho, João Pedro Alves de Araújo, Jacqueline Marcia Boccacino, Rebeca Piatniczka Iglesia, Maria Isabel Melo-Escobar, Mariana Brandão Prado, Marcelo Falchetti, Frederico Moraes Ferreira, Helder Nakaya, Tiago Góss Dos Santos, Edroaldo Lummertz da Rocha, Flávio H Beraldo, Vania F Prado, Marco A M Prado

Laboratory of Neurobiology and Stem cells, Department of Cell and Developmental Biology; Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil. Laboratory of Neurobiology and Stem cells, Department of Cell and Developmental Biology; Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil. Robarts Research Institute, The University of Western Ontario, London, ON, Canada. Program in Neuroscience, The University of Western Ontario, London, ON, Canada. Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, SC, Brazil. LIM50, Division of Pathology, University of São Paulo School of Medicine, São Paulo, SP, Brazil. Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil. Hospital Israelita Albert Einstein, São Paulo, SP, Brazil. A.C. Camargo Cancer Center, Centro Internacional de Pesquisa, Sao Paulo, SP, Brazil. 10Department of Physiology and Pharmacology, The University of Western Ontario, London, ON, Canada. Department of Anatomy and Cell Biology, The University of Western Ontario, London, ON, Canada. Contributed equally.

Service type: Stock strains

Abstract

Proteostasis, maintained by a network of molecular chaperones, plays a central role in cell biology, and has emerged as a critical mechanism underlying pluripotency and development. The stress-inducible phosphoprotein 1 (STIP1) is a co-chaperone essential for proteostasis. STIP1 knockout causes embryonic lethality in mice, but its precise function during embryogenesis remains poorly understood. Here, we investigate the role of STIP1 in early development using in silico and cell-based approaches. Single-cell RNA sequencing data reveals that Stip1 is co-expressed with pluripotency genes in mouse embryos, suggesting a role in stem cell maintenance. To test this, we generated mouse embryonic stem cells (mESCs) from genetically modified mice with altered Stip1/STIP1 expression. STIP1 depletion in mESCs decreases the expression of pluripotency markers, reduces proliferation, and induces apoptosis and genomic instability, whereas its overexpression enhances pluripotency markers expression, promotes proliferation, and confers protection against cellular stress. Moreover, proteins involved in cell cycle progression and DNA damage response are differentially regulated in mESCs, depending on STIP1 levels. Our findings highlight STIP1 as a pivotal regulator of the pluripotent phenotype, early embryogenesis, and cellular resilience, advancing our understanding of proteostasis in stem cell biology and organismal development, with potential implications for disease modeling and regenerative medicine.

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