The Comparison of Normoxic and Hypoxic Mesenchymal Stem Cells in Regulating Platelet-derived Growth Factors and Collagen Serial Levels in Skin Excision Animal Models

Erni Daryanti; Agung Putra; Titik Sumarawati; Nur Dina Amalina; Ardi Prasetio; Husni Ahmad Sidiq

doi:10.3889/oamjms.2023.10966

Authors

Erni Daryanti Department of Biomedical Science, Medical Faculty, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia
Agung Putra Stem Cell and Cancer Research (SCCR), Medical Faculty, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia; Department of Pathology, Medical Faculty, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia; Department of Postgraduate Biomedical Science, Medical Faculty, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia https://orcid.org/0000-0003-4261-9437
Titik Sumarawati Department of Postgraduate Biomedical Science, Medical Faculty, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia
Nur Dina Amalina Stem Cell and Cancer Research (SCCR), Medical Faculty, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia; Pharmacy Study Program, Faculty of Mathematics and Natural Sciences, Universitas Negeri Semarang, Semarang, Indonesia
Ardi Prasetio Stem Cell and Cancer Research (SCCR), Medical Faculty, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia
Husni Ahmad Sidiq Stem Cell and Cancer Research (SCCR), Medical Faculty, Sultan Agung Islamic University (UNISSULA), Semarang, Indonesia

DOI:

https://doi.org/10.3889/oamjms.2023.10966

Keywords:

Collagen, Hypoxia, Mesenchymal stem cells, Platelet-derived growth factors, Skin healing

Abstract

BACKGROUND: The healing process of a skin excisions involves a complex cascade of cellular responses to reverse skin integrity formation. These processes require growth factors particularly platelet-derived growth factors (PDGF). On the other hand, hypoxia- preconditioned mesenchymal stem cells (MSCs) could secrete growth factors that notably contribute to wound healing acceleration, characterized by the enhancement of collagen density.

AIM: This study was aimed to investigate the role of hypoxia-preconditioned MSCs in regulating the serial levels of PDGF associated with the enhancement of collagen density in the skin excision animal models.

METHODS: Twenty-seven male Wistar rats of skin excision were created as animal models. The animals were randomly assigned into four groups consisting of two treatment groups (treated by normoxia-preconditioned MSCs as T1 and hypoxia-preconditioned MSCs as T2), positive control (treated with phosphate-buffered saline) and sham (non-treated and healthy rats). PDGF levels were examined by ELISA. The collagen density was determined using Masson‘s trichrome staining.

RESULTS: This study showed that there was a significant increase in PDGF levels on days 3 and 6 after hypoxia- preconditioned MSCs treatment. In line with these findings, the collagen density was also increased significantly after hypoxia-preconditioned MSCs treatment on days 3, 6, and 9.

CONCLUSION: Hypoxia-preconditioned MSCs could regulate the serial PDGF levels that lead to the enhancement of collagen density in the skin excision rat’s model.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Schreier C, Rothmiller S, Scherer MA, Rummel C, Steinritz D, Thiermann H, et al. Mobilization of human mesenchymal stem cells through different cytokines and growth factors after their immobilization by sulfur mustard. Toxicol Lett. 2018;293:105-11. https://doi.org/10.1016/j.toxlet.2018.02.011 PMid:29426001

Han C, Cheng B, Wu P. Clinical guideline on topical growth factors for skin wounds. Burn Trauma. 2020;8:tkaa035. https://doi.org/10.1093/burnst/tkaa035 PMid:33015207

Ho CH, Lan CW, Liao CY, Hung SC, Li HY, Sung YJ. Mesenchymal stem cells and their conditioned medium can enhance the repair of uterine defects in a rat model. J Chin Med Assoc. 2018;81(3):268-76. https://doi.org/10.1016/j.jcma.2017.03.013 PMid:28882732

Wang S, Mo M, Wang J, Sadia S, Shi B, Fu X, et al. Platelet-derived growth factor receptor beta identifies mesenchymal stem cells with enhanced engraftment to tissue injury and pro-angiogenic property. Cell Mol Life Sci. 2018;75(3):547-61. https://doi.org/10.1007/s00018-017-2641-7 PMid:28929173

Yustianingsih V, Sumarawati T, Putra A. Hypoxia enhances self-renewal properties and markers of mesenchymal stem cells. 2019;38(3):164-71. https://doi.org/10.18051/UnivMed.2019.v38.164-171

Fu X, Chen Y, Xie FN, Dong P, Liu WB, Cao Y, et al. Comparison of immunological characteristics of mesenchymal stem cells derived from human embryonic stem cells and bone marrow. Tissue Eng Part A. 2015;21:616-26. https://doi.org/10.1089/ten.TEA.2013.0651 PMid:25256849

Hu C, Zhao L, Duan J, Li L. Strategies to improve the efficiency of mesenchymal stem cell transplantation for reversal of liver fibrosis. J Cell Mol Med. 2019;23(3):1657-70. https:/doi.org/10.1111/jcmm.14115 PMid:30635966

Sabry D, Mohamed A, Monir M, Ibrahim HA. The effect of mesenchymal stem cells-derived microvesicles on the treatment of experimental CCL4 induced liver fibrosis in rats. Int J Stem Cells. 2019;12(3):400-9. https://doi.org/10.15283/ijsc18143 PMid:31474025

Muhar AM, Putra A, Warli SM, Munir D. Hypoxia-mesenchymal stem cells inhibit intra-peritoneal adhesions formation by upregulation of the il-10 expression. Open Access Maced J Med Sci. 2019;7(23):3937-43. https://doi.org/10.3889/oamjms.2019.713 PMid:32165932

Zhao G, Liu F, Liu Z, Zuo K, Wang B, Zhang Y, et al. MSC-derived exosomes attenuate cell death through suppressing AIF nucleus translocation and enhance cutaneous wound healing. Stem Cell Res Ther. 2020;11(1):174. https://doi.org/10.1186/s13287-020-01616-8 PMid:32393338

Al-Shaibani MB, Dickinson A, Nong-Wang X, Tulah AS, Lovat PE. Effect of conditioned media from mesenchymal stem cells (MSC-CM) on wound healing using a prototype of a fully humanized 3D skin model. Cytotherapy. 2017;19(5):e23-4. https://doi.org/10.1016/j.jcyt.2017.03.062

Roskoski R Jr. The role of small molecule platelet-derived growth factor receptor (PDGFR) inhibitors in the treatment of neoplastic disorders. Pharmacol Res. 2018;129:65-83. https://doi.org/10.1016/j.phrs.2018.01.021 PMid:29408302

Zarei F, Soleimaninejad M. Role of growth factors and biomaterials in wound healing. Artif Cells Nanomed Biotechnol. 2018;46(supp1):906-11. https://doi.org/10.1080/21691401.2018.1439836 PMid:29448839

Singh S, Young A, McNaught CE. The physiology of wound healing. Surg (United Kingdom). 2017;35(9):473-7. https://doi.org/10.1016/j.mpsur.2017.06.004

Darlan DM, Munir D, Putra A, Jusuf NK. MSCs-released TGFβ1 generate CD4+CD25+Foxp3+ in T-reg cells of human SLE PBMC. J Formos Med Assoc. 2020;120(1 Pt 3):602-8. https://doi.org/10.1016/j.jfma.2020.06.028 PMid:32718891

Trisnadi S, Muhar AM, Putra A, Kustiyah AR. Hypoxia-preconditioned mesenchymal stem cells attenuate peritoneal adhesion through TGF-inhibition. Univ Med. 2020;39(1):97-104. https://doi.org/10.18051/UnivMed.2020.v39.97-104

Al Naem M, Bourebaba L, Kucharczyk K, Röcken M, Marycz K. Therapeutic mesenchymal stromal stem cells: Isolation, characterization and role in equine regenerative medicine and metabolic disorders. Stem Cell Rev Rep. 2020;16(2):301-22. https://doi.org/10.1007/s12015-019-09932-0 PMid:31797146

Putra A, Antari AD, Kustiyah AR, Intan YS, Sadyah NA, Wirawan N, et al. Mesenchymal stem cells accelerate liver regeneration in acute liver failure animal model. Biomed Res Ther. 2018;5(11):2802-10. https://doi.org/10.15419/bmrat.v5i11.498

eegle J, Lakatos K, Kalomoiris S, Stewart H, Isseroff RR, Nolta JA, Fierro FA. Hypoxic preconditioning of mesenchymal stromal cells induces metabolic changes, enhances survival, and promotes cell retention in vivo. Stem cells. 2015;33(6):1818-28.

Madrigal M, Rao KS, Riordan NH. A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods. J Transl Med. 2014;12(1):260. https://doi.org/10.1186/s12967-014-0260-8 PMid:25304688

Putra A. Hypoxia-preconditioned MSCs have super effect in ameliorating renal function on acute renal failure animal mode. Open Access Maced J Med Sci. 2019;7(3):305-10. https://doi.org/10.3889/oamjms.2019.049 PMid:30833992

Li Z, Wei H, Deng L, Cong X, Chen X. Expression and secretion of interleukin-1β, tumour necrosis factor-α and interleukin-10 by hypoxia-and serum-deprivation-stimulated mesenchymal stem cells. FEBS J. 2010;277(18):3688-98. https://doi.org/10.1111/j.1742-4658.2010.07770.x PMid:20681988

He X, Dong Z, Cao Y, Wang H, Liu S, Liao L, et al. MSC-derived exosome promotes M2 polarization and enhances cutaneous wound healing. Stem Cells Int. 2019;2019:7132708. https://doi.org/10.1155/2019/7132708 PMid:31582986

Ahangar P, Mills SJ, Cowin AJ. Mesenchymal stem cell secretome as an emerging cell-free alternative for improving wound repair. Int J Mol Sci. 2020;21(19):7038. https://doi.org/10.3390/ijms21197038 PMid:32987830

Steen EH, Wang X, Balaji S, Butte MJ, Bollyky PL, Keswani SG. The role of the anti-inflammatory cytokine interleukin-10 in tissue fibrosis. Adv Wound Care. 2020;9(4):184-98. https://doi.org/10.1089/wound.2019.1032 PMid:32117582

Rahmani F, Ziaee V, Assari R, Sadr M, Rezaei A, Sadr Z, et al. Interleukin 10 and transforming growth factor beta polymorphisms as risk factors for kawasaki disease: A case-control study and meta-analysis. Avicenna J Med Biotechnol. 2019;11(4):325-33. PMid:31908741

Sun ZL, Feng Y, Zou ML, Zhao BH, Liu SY, Du Y, et al. Emerging role of IL-10 in hypertrophic scars. Front Med (Lausanne). 2020;7:438. https://doi.org/10.3389/fmed.2020.00438 PMid:32974363

Lurier EB, Dalton D, Dampier W, Raman P, Nassiri S, Ferraro NM, et al. Transcriptome analysis of IL-10-stimulated (M2c) macrophages by next-generation sequencing. Immunobiology. 2017;222(7):847-56. https://doi.org/10.1016/j.imbio.2017.02.006 PMid:28318799

Lopes RL, Borges TJ, Zanin RF, Bonorino C. IL-10 is required for polarization of macrophages to M2-like phenotype by mycobacterial DnaK (heat shock protein 70). Cytokine. 2016;85:123-9. https://doi.org/10.1016/j.cyto.2016.06.018 PMid:27337694

Wise LM, Stuart GS, Real NC, Fleming SB, Mercer AA. VEGF Receptor-2 activation mediated by VEGF-E limits scar tissue formation following cutaneous injury. Adv Wound Care. 2018;7(8):283-97. https://doi.org/10.1089/wound.2016.0721 PMid:30087804

Casado-Díaz A, Quesada-Gómez JM, Dorado G. Extracellular vesicles derived from mesenchymal stem cells (MSC) in regenerative medicine: Applications in skin wound healing. Front Bioeng Biotechnol. 2020;8:146. https://doi.org/10.3389/fbioe.2020.00146 PMid:32195233

Larouche J, Sheoran S, Maruyama K, Martino MM. Immune regulation of skin wound healing: Mechanisms and novel therapeutic targets. Adv Wound Care. 2018;7(7):209-31. https://doi.org/10.1089/wound.2017.0761 PMid:29984112

Putra A, Ridwan FB, Putridewi AI, Kustiyah AR, Wirastuti K, Sadyah NA, et al. The role of TNF-α induced MSCs on suppressive inflammation by increasing TGF-β and il-10. Open Access Maced J Med Sci. 2018;6(10):1779-83. https://doi.org/10.3889/oamjms.2018.404 PMid:30455748

Rodriguez-Menocal L, Shareef S, Salgado M, Shabbir A, Van Badiavas E. Role of whole bone marrow, whole bone marrow cultured cells, and mesenchymal stem cells in chronic wound healing. Stem Cell Res Ther. 2015;6(1):24. https://doi.org/10.1186/s13287-015-0001-9 PMid:25881077

Zheng X, Ding Z, Cheng W, Lu Q, Kong X, Zhou X, et al. Microskin-inspired injectable MSC-laden hydrogels for scarless wound healing with hair follicles. Adv Healthc Mater. 2020;9(10):e2000041.

Abreu SC, Weiss DJ, Rocco PR. Extracellular vesicles derived from mesenchymal stromal cells: A therapeutic option in respiratory diseases? Stem Cell Res Ther. 2016;7(1):53. https://doi.org/10.1186/s13287-016-0317-0

Li SN, Wu JF. TGF-β/SMAD signaling regulation of mesenchymal stem cells in adipocyte commitment. Stem Cell Res Ther. 2020;11(1):41. https://doi.org/10.1186/s13287-020-1552-y

Hanna C, Hubchak SC, Liang X, Rozen-Zvi B, Schumacker PT, Hayashida T, et al. Hypoxia-inducible factor-2α and TGF-β signaling interact to promote normoxic glomerular fibrogenesis. Am J Physiol Ren Physiol. 2013;305(9):F1323-31. https://doi.org/10.1152/ajprenal.00155.2013 PMid:23946285

Yang K, Liao Z, Wu Y, Li M, Guo T, Lin J, et al. Curcumin and Glu-GNPs induce radiosensitivity against breast cancer stem-like cells. Biomed Res Int. 2020;2020:3189217. https://doi.org/10.1155/2020/3189217 PMid:33457406

Lan CC. Effects and interactions of increased environmental temperature and UV radiation on photoageing and photocarcinogenesis of the skin. Exp Dermatol. 2019;28:23-7. https://doi.org/10.1111/exd.13818