Apoptotic vesicles of mesenchymal stem cells promote M2 polarization and alleviate early-onset preeclampsia via miR-191-5p.

Background: Macrophages play a crucial role in the development of early-onset preeclampsia (EOPE), which may be closely associated with an imbalance in macrophage M1/M2 polarization. Mesenchymal stem cell (MSC)-derived apoptotic vesicles (apoVs) have anti-inflammatory, tissue repair, and immunomodulatory functions. MSC-apoVs may ameliorate EOPE by regulating macrophage polarization, but the underlying mechanisms remain to be clarified.

Methods: Macrophage infiltration and M1/M2 polarization were first analyzed in the placentas of PE patients and normal pregancies to identify macrophage alterations in EOPE placentas. MSC-apoVs were extracted and characterized. The effects of MSC-apoVs on macrophage polarization and trophoblasts invasion were validated in vivo and in vitro. miRNA transcriptomic sequencing of MSC-apoVs was conducted to identify key miRNAs involved in macrophage M2 polarization and to investigate upstream and downstream regulation factors, which were further validated in vivo and in vitro.

Results: The proportion of M2 macrophages was significantly reduced in EOPE placentas. MSC-apoVs carrying high levels of miR-191-5p recruited macrophages, downregulated CDK6 protein expression, stabilized mitochondrial membrane potential (MMP), and promoted M2 polarization of macrophages. This enhanced the invasion of trophoblasts and improved EOPE pregnancy outcomes in mice, including reduced blood pressure, decreased urine protein, and improved embryo quality. Overexpression of miR-191-5p mimics in MSC-apoVs further alleviated EOPE-related symptoms, whereas inhibition of miR-191-5p reduced the therapeutic effect of MSC-apoVs. Further experiments confirmed that M2 macrophages polarized by MSC-apoVs promote trophoblasts invasion by secreting platelet-derived growth factor-AB (PDGF-AB), which binds to platelet-derived growth factor receptor-beta (PDGFR-β) on trophoblasts, directly activating the downstream PI3K-AKT-mTOR signaling pathway, thereby improving EOPE.

Conclusion: Our findings reveal the crucial role of M2 macrophages in the pathogenesis of EOPE. MSC-apoVs with high miR-191-5p recruit macrophages, downregulate CDK6, stabilize MMP, and promote M2 polarization, increasing PDGF-AB secretion, which enhances trophoblasts invasion and thereby treat EOPE. Therefore, MSC-apoVs therapy may serve as a promising strategy to improve the prognosis of EOPE.