Growth differentiation factor 11 promotes differentiation of MSCs into endothelial-like cells for angiogenesis

Chi Zhang; Yinuo Lin; Qi Liu; Junhua He; Pingping Xiang; Dianliang Wang; Xinyang Hu; Jinghai Chen; Wei Zhu; Hong Yu

doi:10.1111/jcmm.15502

Growth differentiation factor 11 promotes differentiation of MSCs into endothelial-like cells for angiogenesis

J Cell Mol Med. 2020 Aug;24(15):8703-8717. doi: 10.1111/jcmm.15502. Epub 2020 Jun 25.

Authors

Chi Zhang^{1

2}, Yinuo Lin³, Qi Liu^{1

2}, Junhua He^{1

2}, Pingping Xiang^{1

2}, Dianliang Wang⁴, Xinyang Hu^{1

2}, Jinghai Chen^{1

2}, Wei Zhu^{1

2}, Hong Yu^{1

2}

Affiliations

¹ Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
² Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, China.
³ Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
⁴ Stem Cell and Tissue Engineering Research Laboratory, PLA Rocket Force Characteristic Medical Center, Beijing, China.

Abstract

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor-β super family. It has multiple effects on development, physiology and diseases. However, the role of GDF11 in the development of mesenchymal stem cells (MSCs) is not clear. To explore the effects of GDF11 on the differentiation and pro-angiogenic activities of MSCs, mouse bone marrow-derived MSCs were engineered to overexpress GDF11 (MSC^GDF11 ) and their capacity for differentiation and paracrine actions were examined both in vitro and in vivo. Expression of endothelial markers CD31 and VEGFR2 at the levels of both mRNA and protein was significantly higher in MSC^GDF11 than control MSCs (MSC^Vector ) during differentiation. More tube formation was observed in MSC^GDF11 as compared with controls. In an in vivo angiogenesis assay with Matrigel plug, MSC^GDF11 showed more differentiation into CD31⁺ endothelial-like cells and better pro-angiogenic activity as compared with MSC^Vector . Mechanistically, the enhanced differentiation by GDF11 involved activation of extracellular-signal-related kinase (ERK) and eukaryotic translation initiation factor 4E (EIF4E). Inhibition of either TGF-β receptor or ERK diminished the effect of GDF11 on MSC differentiation. In summary, our study unveils the function of GDF11 in the pro-angiogenic activities of MSCs by enhancing endothelial differentiation via the TGFβ-R/ERK/EIF4E pathway.

Keywords: GDF11; angiogenesis; angiogenic therapy; differentiation; endothelial cells; mesenchymal stem cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / genetics
Bone Morphogenetic Proteins / genetics*
Bone Morphogenetic Proteins / metabolism
Cell Differentiation / genetics*
Cell Movement
Cells, Cultured
Endothelial Cells / cytology
Endothelial Cells / metabolism*
Gene Expression
Growth Differentiation Factors / genetics*
Growth Differentiation Factors / metabolism
Hypoxia
MAP Kinase Signaling System
Male
Mesenchymal Stem Cells / cytology*
Mesenchymal Stem Cells / metabolism*
Mice
Neovascularization, Physiologic / genetics*
Vascular Endothelial Growth Factor A / genetics
Vascular Endothelial Growth Factor A / metabolism

Substances

Bone Morphogenetic Proteins
Gdf11 protein, mouse
Growth Differentiation Factors
Vascular Endothelial Growth Factor A