Hypoxic Conditioned Medium from Human Amniotic Fluid-derived Mesenchymal Stem Cells Accelerates Skin Wound Healing Through TGF-β/SMAD2 and PI3K/Akt Pathways

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2014 Jan 9

PMID 24398984

Citations 89

Authors

Eun Kyoung Jun

Qiankun Zhang

Byung Sun Yoon

Jai-Hee Moon

Gilju Lee

Gyuman Park

Phil Jun Kang

Jung Han Lee

Areee Kim

Seungkwon You

Affiliations

Soon will be listed here.

Abstract

In a previous study, we isolated human amniotic fluid (AF)-derived mesenchymal stem cells (AF-MSCs) and utilized normoxic conditioned medium (AF-MSC-norCM) which has been shown to accelerate cutaneous wound healing. Because hypoxia enhances the wound healing function of mesenchymal stem cell-conditioned medium (MSC-CM), it is interesting to explore the mechanism responsible for the enhancement of wound healing function. In this work, hypoxia not only increased the proliferation of AF-MSCs but also maintained their constitutive characteristics (surface marker expression and differentiation potentials). Notably, more paracrine factors, VEGF and TGF-β1, were secreted into hypoxic conditioned medium from AF-MSCs (AF-MSC-hypoCM) compared to AF-MSC-norCM. Moreover, AF-MSC-hypoCM enhanced the proliferation and migration of human dermal fibroblasts in vitro, and wound closure in a skin injury model, as compared to AF-MSC-norCM. However, the enhancement of migration of fibroblasts accelerated by AF-MSC-hypoCM was inhibited by SB505124 and LY294002, inhibitors of TGF-β/SMAD2 and PI3K/AKT, suggesting that AF-MSC-hypoCM-enhanced wound healing is mediated by the activation of TGF-β/SMAD2 and PI3K/AKT. Therefore, AF-MSC-hypoCM enhances wound healing through the increase of hypoxia-induced paracrine factors via activation of TGF-β/SMAD2 and PI3K/AKT pathways.

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References

Jung S, Lee H, Yoon J, Kim S, Kim C, Song H . Upregulation of TGF-beta-induced tissue transglutaminase expression by PI3K-Akt pathway activation in human subconjunctival fibroblasts. Invest Ophthalmol Vis Sci. 2007; 48(5):1952-8. DOI: 10.1167/iovs.06-1164. View

Lee E, Xia Y, Kim W, Kim M, Kim T, Kim K . Hypoxia-enhanced wound-healing function of adipose-derived stem cells: increase in stem cell proliferation and up-regulation of VEGF and bFGF. Wound Repair Regen. 2009; 17(4):540-7. DOI: 10.1111/j.1524-475X.2009.00499.x. View

Kim W, Park B, Sung J, Yang J, Park S, Kwak S . Wound healing effect of adipose-derived stem cells: a critical role of secretory factors on human dermal fibroblasts. J Dermatol Sci. 2007; 48(1):15-24. DOI: 10.1016/j.jdermsci.2007.05.018. View

In t Anker P, Scherjon S, Kleijburg-van der Keur C, Noort W, Claas F, Willemze R . Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. Blood. 2003; 102(4):1548-9. DOI: 10.1182/blood-2003-04-1291. View

Miller G, Chen E . Life stress and diminished expression of genes encoding glucocorticoid receptor and beta2-adrenergic receptor in children with asthma. Proc Natl Acad Sci U S A. 2006; 103(14):5496-501. PMC: 1414639. DOI: 10.1073/pnas.0506312103. View

Moon J, Kwak S, Park G, Jung H, Yoon B, Park J . Isolation and characterization of multipotent human keloid-derived mesenchymal-like stem cells. Stem Cells Dev. 2008; 17(4):713-24. DOI: 10.1089/scd.2007.0210. View

Tsai C, Chen Y, Yew T, Chen L, Wang J, Chiu C . Hypoxia inhibits senescence and maintains mesenchymal stem cell properties through down-regulation of E2A-p21 by HIF-TWIST. Blood. 2010; 117(2):459-69. DOI: 10.1182/blood-2010-05-287508. View

Chernykh E, Shevela E, Leplina O, Tikhonova M, Ostanin A, Kulagin A . Characteristics of bone marrow cells under conditions of impaired innervation in patients with spinal trauma. Bull Exp Biol Med. 2006; 141(1):117-20. DOI: 10.1007/s10517-006-0109-0. View

Meckmongkol T, Harmon R, McKeown-Longo P, Van De Water L . The fibronectin synergy site modulates TGF-beta-dependent fibroblast contraction. Biochem Biophys Res Commun. 2007; 360(4):709-14. PMC: 2034296. DOI: 10.1016/j.bbrc.2007.06.121. View

10.

Carmeliet P, Dor Y, Herbert J, Fukumura D, Brusselmans K, Dewerchin M . Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 1998; 394(6692):485-90. DOI: 10.1038/28867. View

11.

COLTER D, Sekiya I, Prockop D . Identification of a subpopulation of rapidly self-renewing and multipotential adult stem cells in colonies of human marrow stromal cells. Proc Natl Acad Sci U S A. 2001; 98(14):7841-5. PMC: 35429. DOI: 10.1073/pnas.141221698. View

12.

Kern S, Eichler H, Stoeve J, Kluter H, Bieback K . Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells. 2006; 24(5):1294-301. DOI: 10.1634/stemcells.2005-0342. View

13.

Chen J, Crawford R, Chen C, Xiao Y . The key regulatory roles of the PI3K/Akt signaling pathway in the functionalities of mesenchymal stem cells and applications in tissue regeneration. Tissue Eng Part B Rev. 2013; 19(6):516-28. DOI: 10.1089/ten.TEB.2012.0672. View

14.

Prusa A, Hengstschlager M . Amniotic fluid cells and human stem cell research: a new connection. Med Sci Monit. 2002; 8(11):RA253-7. View

15.

Shih N, Jo O, Yanagawa N . Effects of PHEX antisense in human osteoblast cells. J Am Soc Nephrol. 2002; 13(2):394-399. DOI: 10.1681/ASN.V132394. View

16.

Loike J, Cao L, Brett J, Ogawa S, Silverstein S, Stern D . Hypoxia induces glucose transporter expression in endothelial cells. Am J Physiol. 1992; 263(2 Pt 1):C326-33. DOI: 10.1152/ajpcell.1992.263.2.C326. View

17.

Rosova I, Dao M, Capoccia B, Link D, Nolta J . Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. Stem Cells. 2008; 26(8):2173-82. PMC: 3017477. DOI: 10.1634/stemcells.2007-1104. View

18.

Crisostomo P, Wang Y, Markel T, Wang M, Lahm T, Meldrum D . Human mesenchymal stem cells stimulated by TNF-alpha, LPS, or hypoxia produce growth factors by an NF kappa B- but not JNK-dependent mechanism. Am J Physiol Cell Physiol. 2008; 294(3):C675-82. DOI: 10.1152/ajpcell.00437.2007. View

19.

Kho Y, Kim S, Yoon B, Moon J, Kim B, Kwak S . Induction of serum amyloid A genes is associated with growth and apoptosis of HC11 mammary epithelial cells. Biosci Biotechnol Biochem. 2008; 72(1):70-81. DOI: 10.1271/bbb.70374. View

20.

Katritsis D, Sotiropoulou P, Karvouni E, Karabinos I, Korovesis S, Perez S . Transcoronary transplantation of autologous mesenchymal stem cells and endothelial progenitors into infarcted human myocardium. Catheter Cardiovasc Interv. 2005; 65(3):321-9. DOI: 10.1002/ccd.20406. View