Hepatic-derived extracellular vesicles in late pregnancy promote mammary gland development by stimulating prolactin receptor-mediated JAK2/STAT5/mTOR signalling

Abstract

The mammary glands develop rapidly in late pregnancy to prepare adequately for lactation. At this stage the liver is crucial for mammary gland development, and it can achieve distal mammary gland regulation through hepatic factors and hormones. Recently, an increasing number of studies have found that hepatic-derived extracellular vesicles play an essential role in organ-to-organ communication, however, its effect on mammary gland development remains unclear. In this study, we extracted hepatic-derived extracellular vesicles from pregnant (P-hEVs) and non-pregnant mice (NP-hEVs), respectively, and explored their regulatory role on mammary gland development. The results revealed that P-hEVs was able to promote the proliferation and differentiation of HC11 cells. In addition, intraperitoneal injection of P-hEVs into pubertal female mice increased mammary gland weight and promoted mammary gland development. Mechanistically, P-hEVs activated the PI3K/AKT signalling pathway to enhance the proliferation of mammary epithelial cells, and also activated prolactin receptor-mediated JAK2/STAT5/mTOR signalling to promote mammary epithelial cell lactation and the synthesis of milk proteins and milk lipids. Overall, mouse liver during pregnancy can transmit signals to the mammary gland in the form of extracellular vesicles to promote its development and provide for subsequent lactation.