Department of Obstetrics and Gynecology, Women and Children's Hospital of Chongqing Medical University, Chongqing, China.
Department of Toxicology, Joint International Research Laboratory of Reproduction and Development of the Ministry of Education of China, School of Public Health, Chongqing Medical University, Chongqing, China.
Biol Reprod. 2024 Aug 15;111(2):414-426. doi: 10.1093/biolre/ioae064.
The purpose of this study is to investigate the role of high mobility group protein B1 (HMGB1) in placental development and fetal growth.
We employed the Cre-loxP recombination system to establish a placenta-specific HMGB1 knockout mouse model. Breeding HMGB1flox/flox mice with Elf5-Cre mice facilitated the knockout, leveraging Elf5 expression in extra-embryonic ectoderm, ectoplacental cone, and trophoblast giant cells at 12.5 days of embryonic development. The primary goal of this model was to elucidate the molecular mechanism of HMGB1 in placental development, assessing parameters such as placental weight, fetal weight, and bone development. Additionally, we utilized lentiviral interference and overexpression of HMGB1 in human trophoblast cells to further investigate HMGB1's functional role.
Our findings indicate that the HMGB1flox/floxElf5cre/+ mouse displays fetal growth restriction, characterized by decreased placental and fetal weight and impaired bone development. The absence of HMGB1 inhibits autophagosome formation, impairs lysosomal degradation, and disrupts autophagic flux. Depletion of HMGB1 in human trophoblast cells also suppresses cell viability, proliferation, migration, and invasion by inhibiting the ERK signaling pathway. Overexpression of HMGB1 observed the opposite phenotypes.
HMGB1 participates in the regulation of autophagy through the ERK signaling pathway and affects placental development.
本研究旨在探讨高迁移率族蛋白 B1（HMGB1）在胎盘发育和胎儿生长中的作用。
我们采用 Cre-loxP 重组系统构建胎盘特异性 HMGB1 敲除小鼠模型。通过将 HMGB1flox/flox 小鼠与 Elf5-Cre 小鼠杂交，利用 Elf5 在胚胎发育 12.5 天时的胚胎外胚层、胎盘外胚层和滋养层巨细胞中的表达，实现 HMGB1 的敲除。该模型的主要目的是阐明 HMGB1 在胎盘发育中的分子机制，评估胎盘重量、胎儿体重和骨骼发育等参数。此外，我们还利用慢病毒干扰和过表达 HMGB1 来进一步研究 HMGB1 的功能作用。
我们的研究结果表明，HMGB1flox/floxElf5cre/+ 小鼠表现出胎儿生长受限，表现为胎盘和胎儿体重减轻以及骨骼发育受损。HMGB1 的缺失抑制自噬体的形成，损害溶酶体的降解，并破坏自噬流。在人滋养层细胞中敲低 HMGB1 也通过抑制 ERK 信号通路抑制细胞活力、增殖、迁移和侵袭。HMGB1 的过表达观察到相反的表型。
HMGB1 通过 ERK 信号通路参与自噬的调节，并影响胎盘发育。
