Human Umbilical Cord Mesenchymal Stem Cell Promotes Angiogenesis via Integrin β1/ERK1/2/HIF-1α/VEGF-A Signaling Pathway for off-the-shelf Breast Tissue Engineering

Abstract

\n Background: Mesenchymal stem cells (MSC) based tissue engineered breast represent the visible future for breast reconstruction after mastectomy. However, autologous MSCs might not be appropriate for the large graft construction due to cell senescence during excessive cell expansion, thus hindering its further off-the-shelf application. As human umbilical cord stem cells (hUCMSCs) have been proved to be safe with low immune response and easily stored, they are ideal for off-the-shelf tissue engineering application. Here, we aim to explore the possibility of umbilical cord mesenchymal stem cells as tissue-engineered breast seed cells. Methods: The allogenic hUCMSCs were injected into transplanted fat tissue with or without breast scaffolds as an alternative for breast tissue engineering in vivo, and its potential mechanism of angiogenesis in vitro was explored.Results: The hUCMSCs promoted proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs) through paracrine process by activating the integrin β1/ERK1/2/HIF-1α/VEGF-A signaling pathway. Histological examination of grafted fat revealed that the group which received hUCMSCs transplantation had more fat tissue ((93.60±2.40) %) and less MAC2+CD206- M1 macrophages ((0.50±0.47) cells/field) compared to control group (fat tissue (45.42±5.96) and macrophage cells/field (5.00±2.23)). Moreover, the cell tracing dye labeled hUCMSCs were confirmed to differentiate into adipocytes and vascular endothelial cells in adipose tissue. Additionally, when applied to the tissue-engineered breast with scaffold, the group treat with hUCMSCs had more adipose tissues and CD31+ cells than the control group.Conclusions: Our findings demonstrate the role of allogeneic hUCMSCs in regenerating adipose tissue and may provide a new strategy to construct tissue engineered breast.