Lactate Promotes the Second Cell Fate Decision in Blastocysts by Prompting Primitive Endoderm Formation Through an Intercellular Positive Feedback Loop That Couples Paracrine FGF Signalling

Xiao Hu; Yawen Tang; Wei Zhao; Juan Liu; Zhize Liu; Qianyin Yang; Meiqiang Chu; Jianhui Tian; Lei An; Shumin Wang

doi:10.1111/cpr.70088

Lactate Promotes the Second Cell Fate Decision in Blastocysts by Prompting Primitive Endoderm Formation Through an Intercellular Positive Feedback Loop That Couples Paracrine FGF Signalling

Cell Prolif. 2025 Jun 27:e70088. doi: 10.1111/cpr.70088. Online ahead of print.

Authors

Xiao Hu^{1

2

3

4

5

6}, Yawen Tang^{1

2

3

4

5}, Wei Zhao^{1

2

3

4

5}, Juan Liu^{1

2

3

4

5

7}, Zhize Liu^{1

2

3

4

5}, Qianyin Yang^{1

2

3

4

5}, Meiqiang Chu^{1

2

3

4

5}, Jianhui Tian^{1

2

3

4

5}, Lei An^{1

2

3

4

5}, Shumin Wang^{1

2

3

4

5}

Affiliations

¹ Frontiers Science Center for Molecular Design Breeding, Of the Ministry of Education, China Agricultural University, Beijing, China.
² Key Laboratory of Animal Genetics, Breeding and Reproduction, Of the Ministry of Agriculture and Rural Affairs, China Agricultural University, Beijing, China.
³ State Key Laboratory of Animal Biotech Breeding, China Agricultural University, Beijing, China.
⁴ National Engineering Laboratory for Animal Breeding, China Agricultural University, Beijing, China.
⁵ College of Animal Science and Technology, China Agricultural University, Beijing, China.
⁶ Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, and Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, People's Republic of China.
⁷ College of Animal Science and Technology, Hunan Provincial Key Laboratory for Genetic Improvement of Domestic Animal, Hunan Agricultural University, Changsha, China.

PMID: 40579118
DOI: 10.1111/cpr.70088

Abstract

Lactate has been widely recognised as an energy source and metabolic by-product, but increasing evidence supports its critical role as a signalling molecule or epigenetic substrate. During early embryogenesis, lactate production increases during the transition from early to late blastocyst, coinciding with the differentiation of inner mass cell (ICM) into epiblast (EPI) and primitive endoderm (PrE), termed the second cell fate decision. However, the role of this hallmark metabolic change in the second cell fate segregation remains unknown. Herein, using in vitro and in vivo models, we found lactate production is preferentially increased in PrE cells and is essential for ICM differentiation into PrE. Mechanically, increased lactate in PrE precursor cells and FGF signalling in EPI precursor cells reciprocally activate each other and synergise to prompt PrE specification, forming an intercellular positive feedback loop essential for this lineage commitment. Additionally, lactate enhanced histone lactylation levels during differentiation into PrE fate. Thus, our findings construct a complex multilayer model in which intracellular metabolite in PrE cooperates with intercellular growth factor signalling from EPI to regulate early embryonic lineage commitment. Highlighting the multifaceted lactate's function, our findings also advance the current knowledge that bridges epigenetic reprogramming and metabolic remodelling during early embryonic development.

Keywords: FGF4; histone lactylation; lactate; pre‐implantation embryo; primitive endoderm.

Abstract

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