Monotropein promotes angiogenesis and inhibits oxidative
stress-induced autophagy in endothelial progenitor cells to
accelerate wound healing
a, b, #
, Cong Mao
a, b, #
, Yiting Lou
, Jianxiang Xu
, Qingqing Wang
, Qian Tang
, Xiaolei Zhang
, Huazi Xu
*, Yongzeng Feng
Department of Orthopedics, The Second Afﬁliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University,
Key Laboratory of Orthopedics of Zhejiang Province, The Second Afﬁliated Hospital of Wenzhou Medical University, Wenzhou,
Received: May 29, 2017; Accepted: September 29, 2017
Attenuating oxidative stress-induced damage and promoting endothelial progenitor cell (EPC) differentiation are critical for ischaemic injuries.
We suggested monotropein (Mtp), a bioactive constituent used in traditional Chinese medicine, can inhibit oxidative stress-induced mitochon-
drial dysfunction and stimulate bone marrow-derived EPC (BM-EPC) differentiation. Results showed Mtp signiﬁcantly elevated migration and
tube formation of BM-EPCs and prevented tert-butyl hydroperoxide (TBHP)-induced programmed cell death through apoptosis and autophagy
by reducing intracellular reactive oxygen species release and restoring mitochondrial membrane potential, which may be mediated via mTOR/
p70S6K/4EBP1 and AMPK phosphorylation. Moreover, Mtp accelerated wound healing in rats, as indicated by reduced healing times, decreased
macrophage inﬁltration and increased blood vessel formation. In summary, Mtp promoted mobilization and differentiation of BM-EPCs and pro-
tected against apoptosis and autophagy by suppressing the AMPK/mTOR pathway, improving wound healing in vivo. This study revealed that
Mtp is a potential therapeutic for endothelial injury-related wounds.
endothelial progenitor cells
Skin wounds caused by trauma, burns and chronic diseases are a
major public health problem around the world, which usually cause
pain, infections and even amputation in millions of patients, resulting
in decreases in quality of life and heavy medical burden [1, 2]. The
major goals of wound repair are to shorten the closure time and
obtain a functional and aesthetically satisfactory scar. Wound healing
is a complex process that is classically divided into three stages,
including inﬂammation, proliferation and remodelling. This process
requires the efforts of multiple cells, growth factors and extracellular
signals . Angiogenesis is critical for wound healing, especially
those from chronic and ischemic injuries. Newly formed blood ves-
sels are essential for tissue repair because they can support cells at
the wound site with nutrition and oxygen. EPCs, a type of bone
marrow mononuclear progenitor cell, can differentiate into endothelial
lineage cells and exert vasculogenic effects ; moreover, endothelial
progenitor cells (EPCs) are recruited and stimulated to participate in
angiogenesis after tissue wounding .
In recent studies, EPC transplantation induced angiogenesis and
increased functional blood supply in the ischemic tissues . How-
ever, clinical studies have reported reduced numbers of EPCs and
impaired endothelial function in diabetic patients . Furthermore,
endothelial injury can be caused by oxidative stress, endoplasmic
reticulum stress and damage to the immune system [8, 9]. Geneti-
cally induced oxidative stress in mice could cause placental angiodys-
plasia . Based on several lines of evidence, oxidative stress
induced autophagy upon nutrient deprivation; treatment with
These two authors contributed equally to this study.
*Correspondence to: Huazi XU, M.D.
Yongzeng FENG, Ph.D.
ª 2017 The Authors.
Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use,
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J. Cell. Mol. Med. Vol 22, No 3, 2018 pp. 1583-1600