Substance P accelerates wound healing in type 2 diabetic mice through endothelial progenitor cell mobilization and Yes-associated protein activation

Published on May 1, 2017in Molecular Medicine Reports2.1
· DOI :10.3892/MMR.2017.6344
Jihyun Um6
Estimated H-index: 6
(Kyung Hee University),
Jinyeong Yu5
Estimated H-index: 5
(Kyung Hee University),
Ki-Sook Park16
Estimated H-index: 16
(Kyung Hee University)
Sources
Abstract
: Wound healing is delayed in diabetes due to a number of factors, including impaired angiogenesis and poor dermal healing. The present study demonstrated that subcutaneous administration of substance P (SP) accelerates wound healing in db/db type 2 diabetic mice (db/db mice). SP injection (10 nM/kg, subcutaneously) enhanced angiogenesis, induced the mobilization of endothelial progenitor cells (EPCs) and increased the number of EPC‑colony forming units (EPC‑CFUs) in the bone marrow of db/db mice. Immunohistochemistry was performed to check the effects of SP on the cellular proliferation and the subcellular localization of Yes-associated protein (YAP) in the wound dermis. SP also upregulated cellular proliferation in the injured dermis of db/db mice. Compared with the control group, an increased number of cells in the wound dermis of SP-treated mice exhibited nuclear localization of YAP, which induces cellular proliferation. The results of the current study indicate that subcutaneous administration of SP may be a promising therapeutic strategy to treat diabetic wounds exhibiting impaired angiogenesis and dysfunctional dermal wound healing.
📖 Papers frequently viewed together
83 Citations
20134.13Gene Therapy
16 Authors (Junkai Du, ..., John W. Harmon)
25 Citations
324 Citations
References23
Newest
#1Jihyun Um (Kyung Hee University)H-Index: 6
#2Nunggum Jung (Kyung Hee University)H-Index: 4
Last. Ki-Sook Park (Kyung Hee University)H-Index: 16
view all 6 authors...
Wound healing is essential for the survival and tissue homeostasis of unicellular and multicellular organisms. The current study demonstrated that the neuropeptide substance P (SP) accelerated the wound healing process, particularly in the skin. Subcutaneous treatment of SP accelerated wound closing, increased the population of α-smooth muscle actin positive myofibroblasts, and increased extracellular matrix deposition at the wound site. Moreover, SP treatment enhances angiogenesis without a loc...
16 CitationsSource
#1Carsten G. Hansen (UCSD: University of California, San Diego)H-Index: 17
#2Toshiro Moroishi (UCSD: University of California, San Diego)H-Index: 17
Last. Kun-Liang Guan (UCSD: University of California, San Diego)H-Index: 155
view all 3 authors...
The Hippo pathway is a potent regulator of cellular proliferation, differentiation, and tissue homeostasis. Here we review the regulatory mechanisms of the Hippo pathway and discuss the function of Yes-associated protein (YAP)/transcriptional coactivator with a PDZ-binding domain (TAZ), the prime mediators of the Hippo pathway, in stem cell biology and tissue regeneration. We highlight their activities in both the nucleus and the cytoplasm and discuss their role as a signaling nexus and integrat...
280 CitationsSource
#1Claas Baustian (National University of Ireland, Galway)H-Index: 4
#2Shirley A. Hanley (National University of Ireland, Galway)H-Index: 11
Last. Rhodri Ceredig (National University of Ireland, Galway)H-Index: 59
view all 3 authors...
Introduction Conventionally cultured mouse bone marrow mesenchymal stromal cells (mBM-MSC) are a heterogeneous population that often initially contain contaminating haematopoietic cells. Variability in isolation methods, culture protocols and the lack of specific mBM MSC markers might explain this heterogeneity. The aim of this study is to optimise the isolation, culture conditions and selection of mBM-MSC.
29 CitationsSource
#1Ermelindo C. Leal (UC: University of Coimbra)H-Index: 22
#2Eugenia Carvalho (UC: University of Coimbra)H-Index: 33
Last. Aristidis Veves (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 77
view all 13 authors...
Diabetic foot ulceration is a major complication of diabetes. Substance P (SP) is involved in wound healing, but its effect in diabetic skin wounds is unclear. We examined the effect of exogenous SP delivery on diabetic mouse and rabbit wounds. We also studied the impact of deficiency in SP or its receptor, neurokinin-1 receptor, on wound healing in mouse models. SP treatment improved wound healing in mice and rabbits, whereas the absence of SP or its receptor impaired wound progression in mice....
83 CitationsSource
#1Vinay Kant (IVRI: Indian Veterinary Research Institute)H-Index: 15
#2Dinesh Kumar (IVRI: Indian Veterinary Research Institute)H-Index: 23
Last. S. K. Tandan (IVRI: Indian Veterinary Research Institute)H-Index: 7
view all 8 authors...
Abstract Substance P (SP) is known to stimulate angiogenesis, fibroblasts proliferation and expressions of cytokines and growth factors involved in wound healing. However, SP level reduces in dermis in diabetics and, hence, it was hypothesized that exogenously applied SP could be helpful in improving wound healing in diabetic rats. Excision skin wound was created on the back of diabetic rats and rats were divided into three groups i.e. (i) saline-, (ii) gel- and (iii) SP-treated. Normal saline, ...
33 CitationsSource
#1Lingling Yang (Academy of Medical Sciences, United Kingdom)H-Index: 15
#2Guohu Di (Academy of Medical Sciences, United Kingdom)H-Index: 9
Last. Qingjun Zhou (Academy of Medical Sciences, United Kingdom)H-Index: 18
view all 9 authors...
Substance P (SP) is a neuropeptide, predominantly released from sensory nerve fibers, with a potentially protective role in diabetic corneal epithelial wound healing. However, the molecular mechanism remains unclear. We investigated the protective mechanism of SP against hyperglycemia-induced corneal epithelial wound healing defects, using type 1 diabetic mice and high glucose-treated corneal epithelial cells. Hyperglycemia induced delayed corneal epithelial wound healing, accompanied with atten...
95 CitationsSource
#1Barry M. Gumbiner (UVA: University of Virginia)H-Index: 83
#2Nam-Gyun Kim (UVA: University of Virginia)H-Index: 22
The Hippo-YAP pathway mediates the control of cell proliferation by contact inhibition as well as other attributes of the physical state of cells in tissues. Several mechanisms sense the spatial and physical organization of cells, and function through distinct upstream modules to stimulate Hippo-YAP signaling: adherens junction or cadherin–catenin complexes, epithelial polarity and tight junction complexes, the FAT-Dachsous morphogen pathway, as well as cell shape, actomyosin or mechanotransduct...
183 CitationsSource
#1Min Jung Lee (Yonsei University)H-Index: 17
#2Mi Ran Byun (KU: Korea University)H-Index: 13
Last. Han Sung Jung (Yonsei University)H-Index: 34
view all 5 authors...
The Hippo signaling pathway regulates organ size, tissue regeneration, and stem cell self-renewal. The two key downstream transcription coactivators in this pathway, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), mediate the major gene regulation and biological functions of the Hippo pathway. The biological functions of YAP and TAZ in many tissues are known; however, their roles in skin wound healing remain unclear. To analyze whether YAP and/or TAZ ar...
108 CitationsSource
#1Kieran F. Harvey (University of Melbourne)H-Index: 36
#2Xiaomeng Zhang (University of Melbourne)H-Index: 13
Last. David Thomas (University of Melbourne)H-Index: 99
view all 3 authors...
A wealth of recent studies has characterized roles for the Hippo pathway in diverse cancer-relevant processes. This Review discusses our latest understanding of Hippo pathway signalling in cancer, including mechanisms of pathway disruption in cancer, and the opportunities and challenges for therapeutic intervention.
995 CitationsSource
#1Fa-Xing Yu (UCSD: University of California, San Diego)H-Index: 26
#2Kun-Liang Guan (UCSD: University of California, San Diego)H-Index: 155
Control of cell number is crucial in animal development and tissue homeostasis, and its dysregulation may result in tumor formation or organ degeneration. The Hippo pathway in both Drosophila and mammals regulates cell number by modulating cell proliferation, cell death, and cell differentiation. Recently, numerous upstream components involved in the Hippo pathway have been identified, such as cell polarity, mechanotransduction, and G-protein-coupled receptor (GPCR) signaling. Actin cytoskeleton...
776 CitationsSource
Cited By13
Newest
#1Nicole C. Nowak (NU: Northwestern University)
#2Daniela M. Menichella (NU: Northwestern University)H-Index: 13
Last. Amy S. Paller (NU: Northwestern University)H-Index: 35
view all 4 authors...
Type 2 diabetes (T2D) is associated with several potential comorbidities, among them impaired wound healing, chronic ulcerations, and the requirement for lower extremity amputation. Disease-associated abnormal cellular responses, infection, immunological and microvascular dysfunction, and peripheral neuropathy are implicated in the pathogenesis of the wound healing impairment and the diabetic foot ulcer. The skin houses a dense network of sensory nerve afferents and nerve-derived modulators, whi...
Source
#1Cameron R. Moattari (Cornell University)
#2Richard D. Granstein (Cornell University)H-Index: 59
Humans are exposed to varying amounts of ultraviolet radiation (UVR) through sunlight. UVR penetrates into human skin leading to release of neuropeptides, neurotransmitters and neuroendocrine hormones. These messengers released from local sensory nerves, keratinocytes, Langerhans cells (LCs), mast cells, melanocytes and endothelial cells (ECs) modulate local and systemic immune responses, mediate inflammation and promote differing cell biologic effects. In this review, we will focus on both anim...
Source
#1Suneel KumarH-Index: 18
#2Yuying TanH-Index: 6
Last. Francois BerthiaumeH-Index: 54
view all 3 authors...
Pressure ulcers (PUs) or sores are a secondary complication of diabetic neuropathy and traumatic spinal cord injury (SCI). PUs tend to occur in soft tissues located around bony prominences and may heal slowly or not at all. A common mechanism underlying impaired healing of PUs may be dysfunction of the local neurovascular system including deficiency of essential neuropeptides, such as substance P (SP). Previous studies indicate that disturbance in cutaneous sensory innervation leads to a defect ...
Source
#1Wen-ting Gao (Third Military Medical University)H-Index: 1
#2Xuetao Yang (Third Military Medical University)H-Index: 5
Last. Ce Yang (Third Military Medical University)H-Index: 11
view all 7 authors...
Background Our previous studies have proved the efficient exogenous repairing responses via bone marrow stem and progenitor cells (BMSPCs). However, the trafficking of endogenous bone marrow stem and progenitor cells to and from the bone marrow (BM) is a highly regulated process that remains to be elucidated. We aimed to study the relative importance of the hypothalamic-pituitary-adrenal (HPA) axis in the glucocorticoid-induced BMSPC mobilization. Methods The circulating mesenchymal stem cells (...
Source
#1Sang-Min Baek (Kyung Hee University)H-Index: 1
#2Ki-Young Kim (Kyung Hee University)H-Index: 17
Last. Seung-Young Yu (Kyung Hee University)H-Index: 13
view all 6 authors...
Type 2 diabetic mellitus (T2DM) is characterized by systemic inflammation and insulin resistance due to obesity, and this leads to critical complications, including retinopathy and nephropathy. This study explored the therapeutic effect of substance-p (SP), a neuropeptide, on T2DM progression and its complications. To examine whether SP affects glucose metabolism, lipid metabolism, systemic inflammation, and retinopathy, Otsuka Long-Evans Tokushima Fatty rats (OLETF, 27 weeks old) with chronic i...
Source
#1Holly N. Wilkinson (Hull York Medical School)H-Index: 8
#2Matthew J. Hardman (Hull York Medical School)H-Index: 33
Wound healing is a complex, dynamic process supported by a myriad of cellular events that must be tightly coordinated to efficiently repair damaged tissue. Derangement in wound-linked cellular beha...
7 CitationsSource
#1Wei Zhang (Tianjin Medical University)H-Index: 2
#2Hao Jiang (Tianjin Medical University)H-Index: 1
Last. Yichun Kong (Tianjin Medical University)H-Index: 2
view all 3 authors...
Abstract The purpose of this study was to investigate the role of exosomes derived from platelet-rich plasma (PRP-Exos) in the regulation of the fibrogenic activity of Muller cells and the underlying mechanism. We studied the effects of PRP-Exos on the fibrogenic activity of human retinal Muller cells (hMCs) in vitro. PRP-Exos were isolated from the plasma of diabetic rats (DM-PRP-Exos) and normal control rats (Nor-PRP-Exos) and then observed by transmission electron microscopy. After treatment ...
3 CitationsSource
#1Georgios Theocharidis (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 6
#2Aristidis Veves (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 77
Abstract Lower extremity ulcerations represent a major complication in diabetes mellitus and involve multiple physiological factors that lead to impairment of wound healing. Neuropeptides are neuromodulators implicated in various processes including diabetic wound healing. Diabetes causes autonomic and small sensory nerve fibers neuropathy as well as inflammatory dysregulation, which manifest with decreased neuropeptide expression and a disproportion in pro- and anti- inflammatory cytokine respo...
5 CitationsSource
#1Yulong Zhang (Third Military Medical University)H-Index: 6
#1Yulong Zhang (Southwest General Health Center)H-Index: 1
Last. Zhiqiang Yuan (Southwest General Health Center)H-Index: 1
view all 6 authors...
Background High-mobility group box1 (HMGB1) is a cytokine that has been demonstrated to have an important role in inducing migration and homing of endothelial progenitor cells (EPCs) in the process of neovascularization during wound healing, but its specific mechanism remains elusive. The aim of this study was to investigate the effects of the HMGB-RAGE axis in EPC migration, as well as the underlying molecular mechanism responsible for these effects.
4 CitationsSource
#1Muhammad ShafiqH-Index: 16
#2Lina Wang (NKU: Nankai University)H-Index: 14
Last. Soo Hyun Kim (KIST: Korea Institute of Science and Technology)H-Index: 64
view all 9 authors...
: In situ blood vessel regeneration through host stem/progenitor cell mobilization may hold great promise for vascular reconstruction. Neuropeptide substance P (SP) has been shown to accelerate tissue repair by endogenous cell mobilization and recruitment. This study was aimed to evaluate the vascular regeneration potential of SP and heparin co-tethered vascular grafts. Polycaprolactone (PCL), PCL/SP-conjugated poly(L-lactide-co-e-caprolactone) (PLCL-SP) (SP), and PCL/PLCL-SP/heparin-conjugated ...
6 CitationsSource