Stem Cell Therapy in Wound Healing and Tissue Regeneration

Anna Meiliana, Nurrani Mustika Dewi, Andi Wijaya

Abstract


BACKGROUND: Recent advances in our basic knowledge of the tissue damage and regeneration pathology have combined with a remarkable progress in stem cell biology so the prospect of clinical tissue repair strategies is a tangible reality. We tried to describe a better view about mesenchymal stem cell (MSC) mechanisms in wound healing and tissue regeneration, sending any ideas for next advanced therapies.

CONTENT: Sustaining injury, whether minor or major, is part of every organism life. Therefore, efficient response mechanisms to damage have developed. Wound healing is a perplexing multi-step processes which can be divided into three major phases: inflammation, proliferation, and scar formation/remodeling. Though the compartementalization of this process into discrete stages give the illusion of simplicity, but in reality it is much more complicated. So that efficient healing can occur, complex interactions between multiple cell types, soluble factors and extracellular matrix components are required to rebuild the tissue. Even under optimal conditions, the healing process drives to fibrosis or scar. The latest technology that makes a huge difference in the wound healing process is stem cell therapy, which offers a novel approach to many diseases.

SUMMARY: Wound healing therapies continue to rapidly evolve, with advances in basic science and engineering research heralding the development of new therapies, as well as ways to modify existing treatments. Stem cell-based therapy is one of the most promising therapeutic concepts for wound healing. Advances in stem cell biology have enabled researchers and clinicians alike with access to cells capable of actively modulating the healing response. 

KEYWORDS: wound healing, tissue regeneration, stem cells therapy


Full Text:

PDF

References


Aurora AB, Olson EN. Immune modulation of stem cells and regeneration. Cell Stem Cell. 2014; 15: 14-25, CrossRef.

Watt FM, Driskell RR. The therapeutic potential of stem cells. Philos Trans R Soc Lond B Biol Sci. 2010; 365: 155-63, CrossRef.

Lane SW, Williams DA, Watt FM. Modulating the stem cell niche for tissue regeneration. Nat Biotechnol. 2014; 32: 795-803, CrossRef.

Meiliana A, Dewi NM, Wijaya A. In search for anti-aging strategy: can we rejuvenate our aging stem cells? Indones Biomed J. 2015; 7: 57-72, CrossRef.

Forbes SJ, Rosenthal N. Preparing the ground for tissue regeneration: from mechanism to therapy. Nat Med. 2014; 20: 857-69, CrossRef.

Zielins ER, Atashroo DA, Maan ZN, Duscher D, Walmsley GG, Hu M, et al. Wound healing: an update. Regen Med. 2014; 9: 817-30, CrossRef.

Sonnemann KJ, Bement WM. Wound repair: toward understanding and integration of single-cell and multicellular wound responses. Annu Rev Cell Dev Biol. 2011; 27: 237-63, CrossRef.

Cordeiro JV, Jacinto A. The role of transcription-independent damage signals in the initiation of epithelial wound healing. Nat Rev Mol Cell Biol. 2013; 14: 249-62, CrossRef.

Meiliana A, Wijaya A. Endothelial progenitor cells in diabetic vasculopathy. Indones Biomed J. 2009; 1: 4-23, CrossRef.

Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med. 1999; 341: 738-46, CrossRef.

Aarabi S, Longaker MT, Gurtner GC. Hypertrophic scar formation following burns and trauma: new approaches to treatment. PLoS Med. 2007; 4: e234, CrossRef.

Konigova R, Rychterova V. Marjolin’s ulcer. Acta Chir Plast. 2000; 2: 91-4, PMID.

Trent JT, Kirsner RS. Wounds and malignancy. Adv Skin Wound Care. 2003; 16: 31-4, CrossRef.

Colwell AS, Longaker MT, Lorenz HP. Fetal wound healing. Front Biosci. 2003; 8: s1240-8, CrossRef.

Gurtner GC, Callaghan MJ, Longaker MT. Progress and potential for regenerative medicine. Annu Rev Med. 2007; 58: 299-312, CrossRef.

Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008; 435: 314-21, CrossRef.

King RS, Newmrk PA. The cell biology of regeneration. J Cell Biol. 2012; 196: 553-62, CrossRef.

Levin M. Bioelectric mechanisms in regeneration: Unique aspects and future perspectives. Semin Cell Dev Biol. 2009; 20: 543-56, CrossRef.

Bergmann A, Steller H. Apoptosis, stem cells, and tissue regeneration, Sci Signal. 2010; 3: re8, CrossRef.

Hwang JS, Kobayashi C, Agata K, Ikeo K, Gojobori T. Detection of apoptosis during planarian regeneration by the expression of

apoptosis-related genes and TUNEL assay. Gene. 2004; 333: 15-25, CrossRef.

Vlaskalin T, Wong CJ, Tsilfidis C. Growth and apoptosis during larval forelimb development and adult forelimb regeneration in the newt (Notophthalmus viridescens). Dev Genes Evol. 2004; 214: 423-31, CrossRef.

Tseng AS, Adams DS, Qiu D, Koustubhan P, Levin M. Apoptosis is required during early stages of tail regeneration in Xenopus laevis. Dev Biol. 2007; 301: 62-9, CrossRef.

Chera S, Ghila L, Dobretz K, Wenger Y, Bauer C, Buzgariu W, et al. Apoptotic cells provide an unexpected source of Wnt3 signaling to drive hydra head regeneration. Dev Cell. 2009; 17: 279-89, CrossRef.

Pellettieri J, Fitzgerald P, Watanabe S, Mancuso J, Green DR, Sánchez Alvarado A. Cell death and tissue remodeling in planarian regeneration. Dev Biol. 2010; 338: 76-85, CrossRef.

Pérez-Garijo A, Shlevkov E, Morata G. The role of Dpp and Wg in compensatory proliferation and in the formation of hyperplastic overgrowths caused by apoptotic cells in the Drosophila wing disc. Development. 2009; 136: 1169-77, CrossRef.

Bergantiños C, Corominas M, Serras F. Cell death-induced regeneration in wing imaginal discs requires JNK signalling. Development. 2010; 137: 1169-79, CrossRef.

Morata G, Shlevkov E, Pérez-Garijo A. Mitogenic signaling from apoptotic cells in Drosophila. Dev Growth Differ. 2011; 53: 168-76, CrossRef.

Jiang H, Patel PH, Kohlmaier A, Grenley MO, McEwen DG, BA Edgar. Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut. Cell. 2009; 137: 1343-55, CrossRef.

Valentin-Vega YA, Okano H, Lozano G. The intestinal epithelium compensates for p53-mediated cell death and guarantees organismal survival. Cell Death Differ. 2008; 15: 1772-81, CrossRef.

Gu Y, Forostyan T, Sabbadini R, Rosenblatt J. Epithelial cell extrusion requires the sphingosine-1-phosphate receptor 2 pathway. J Cell Biol. 2011; 193: 667-76, CrossRef.

Riehle KJ, Dan YY, Campbell JS, Fausto N. New concepts in liver regeneration. J Gastroenterol Hepatol. 2011; 26 (Suppl 1): 203-12, CrossRef.

Jopling C, Sleep E, Raya M, Martí M, Raya A, Izpisúa Belmonte JC. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature. 2010; 464: 606-9, CrossRef.

Kikuchi K, Holdway JE, Werdich AA, Anderson RM, Fang Y, Egnaczyk GF, et al. Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature. 2010; 464: 601-5, CrossRef.

Baum CL, Arpey CJ. Normal cutaneous wound healing: clinical correlation with cellular and molecular events. Dermatol Surg. 2005; 31: 674-86, CrossRef.

Wilgus TA, Roy S, McDaniel JC. Neutrophils and wound repair: positive actions and negative reactions. Adv Wound Care. 2013; 2: 379-88, CrossRef.

Sindrilaru A, Scharffetter-Kochanek K. Disclosure of the culprits: macrophages-versatile regulators of wound healing. Adv Wound Care. 2013; 2: 357-68, CrossRef.

Bao P, Kodra A, Tomic-Canic M, Golinko MS, Ehrlich HP, Brem H. The role of vascular endothelial growth factor in wound healing. J Surg Res. 2009; 153: 347-58, CrossRef.

Raja, Sivamani K, Garcia MS, Isseroff RR. Wound re-epithelialization: modulating keratinocyte migration in wound healing. Front Biosci. 2007; 12: 2849-68, CrossRef.

Midgley AC, Rogers M, Hallett MB, Clayton A, Bowen T, Phillips AO, et al. Transforming growth factor-beta1 (TGF-beta1)-stimulated fibroblast to myofibroblast differentiation is mediated by hyaluronan (HA)-facilitated epidermal growth factor receptor (EGFR) and CD44 co-localization in lipid rafts. J Biol Chem. 2013; 288: 14824-38, CrossRef.

Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012; 18: 1028-40, CrossRef.

Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol. 2003; 200: 500-3, CrossRef.

Demidova-Rice TN, Hamblin MR, Herman IM. Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 1: normal and chronic wounds: biology, causes, and approaches to care. Adv Skin Wound Care. 2012; 25: 304-14, CrossRef.

Duffield JS, Lupher M, Thannickal VJ, Wynn TA. Host responses in tissue repair and fibrosis. Annu Rev Pathol. 2013; 8: 241-76, CrossRef.

Rennert RC, Rodrigues M, Wong VW, Duscher D, Hu M, Maan Z, et al. Biological therapies for the treatment of cutaneous wounds: Phase III and launched therapies. Expert Opin Biol Ther. 2013; 13: 1523-41, CrossRef.

Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol. 2014; 14: 181-94, CrossRef.

Zhu Z, Ding J, Shankowsky HA, Tredget EE. The molecular mechanism of hypertrophic scar. J Cell Commun Signal. 2013; 7: 239-52, CrossRef.

Halim AS, Emami A, Salahshourifar I, Kannan TP. Keloid scarring: understanding the genetic basis, advances, and prospects. Arch Plast Surg. 2012; 39: 184-9, CrossRef.

Al-Attar A, Mess S, Thomassen JM, Kauffman CL, Davison SP. Keloid pathogenesis and treatment. Plast Reconstr Surg. 2006; 117: 286-300, CrossRef.

Ehrlich HP, Desmouliere A, Diegelmann RF, Cohen IK, Compton CC, Garner WL, et al. Morphological and immunochemical differences

between keloid and hypertrophic scar. Am J Pathol. 1994; 145: 105-

, PMID.

Schneider JC, Holavanahalli R, Helm P, Goldstein R, Kowalske K. Contractures in burn injury: defining the problem. J Burn Care Res. 2006; 27: 508-14, CrossRef.

Lawrence JW, Mason ST, Schomer K, Klein MB. Epidemiology and impact of scarring after burn injury: a systematic review of the literature. J Burn Care Res. 2012; 33: 136-46, CrossRef.

Klein L, O'Connor CM, Gattis WA, Zampino M, de Luca L, Vitarelli A, et al. Pharmacologic therapy for patients with chronic heart

failure and reduced systolic function: review of trials and practical

considerations. Am J Cardiol. 2003; 91: 18F-40F, CrossRef.

Wynn TA, Chawla A, Pollard W. Macrophage biology in development, homeostasis and disease. Nature. 2013; 496: 445-55, CrossRef.

Rodero MP, Khosrotehrani K. Skin wound healing modulation by macrophages. Int J Clin Exp Pathol. 2010; 3: 643-53, PMID.

Nucera S, Biziato D, De Palma M. The interplay between macrophages and angiogenesis in development, tissue injury and regeneration. Int J Dev Biol. 2011; 55: 495-503, CrossRef.

Lucas T, Waisman A, Ranjan R, Roes J, Krieg T, Müller W, et al. Differential roles of macrophages in diverse phases of skin repair. J Immunol. 2010; 184: 3964-77, CrossRef.

Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010; 32: 593-604, CrossRef.

Wu Y, Zhao RC, Tredget EE. Concise review: bone marrow-derived stem/progenitor cells in cutaneous repair and regeneration. Stem Cells. 2010; 28: 905-15, CrossRef.

Okuno Y, Nakamura-Ishizu A, Kishi K, Suda T, Kubota Y. Bone marrow-derived cells serve as proangiogenic macrophages but not endothelial cells in wound healing. Blood. 2011; 117: 5264-72, CrossRef.

Sindrilaru A, Peters T, Wieschalka S, Baican C, Baican A, Peter H, et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Invest. 2011; 121: 985-97, CrossRef.

Arnold L, Henry A, Poron F, Baba-Amer Y, van Rooijen N, Plonquet A, et al. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J Exp Med. 2007; 204: 1057-69, CrossRef.

Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med. 2007; 204: 3037-47, CrossRef.

Perdiguero E, Sousa-Victor P, Ruiz-Bonilla V, Jardi M, Caelles C, Serrano AL, et al. p38/MKP-1-regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair. J Cell Biol. 2011; 195: 307-22, CrossRef.

Kotter MR, Li WW, Zhao C, Franklin RJ. Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci. 2006; 26: 328-32, CrossRef.

Lin SL, Li B, Rao S, Yeo EJ, Hudson TE, Nowlin BT, et al. Macrophage Wnt7b is critical for kidney repair and regeneration. Proc Natl Acad Sci USA. 2010; 107: 4194-9, CrossRef.

Stefater JA 3rd, Ren S, Lang RA, Duffield JS. Metchnikoff’s policemen: macrophages in development, homeostasis and regeneration. Trends Mol Med. 2011; 17: 743-52, CrossRef.

Stefater JA 3rd, Rao S, Bezold K, Aplin AC, Nicosia RF, Pollard JW, et al. Macrophage Wnt-Calcineurin-Flt1 signaling regulates mouse wound angiogenesis and repair. Blood. 2013; 121: 2574-8, CrossRef.

Li H, Fu X. Mechanisms of action of mesenchymal stem cells in cutaneous wound repair and regeneration. Cell Tissue Res. 2012; 348: 371-7, CrossRef.

Strioga M, Viswanathan S, Darinskas A, Slaby O, Michalek J. Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev. 2012; 21: 2724-52, CrossRef.

Badiavas EV, Abedi M, Butmarc J, Falanga V, Quesenberry P. Participation of bone marrow derived cells in cutaneous wound healing. J Cell Physiol. 2003; 196: 245-50,

http://dx.doi.org/10.1002/jcp.10260">CrossRef.

Salem HK, Thiemermann C. Mesenchymal stromal cells: current understanding and clinical status. Stem Cells. 2010; 28: 585-96, CrossRef.

Jackson WM, Nesti LJ, Tuan RS. Mesenchymal stem cell therapy for attenuation of scar formation during wound healing. Stem Cell Res Ther. 2012; 3: 20, CrossRef.

Rhett JM, Ghatnekar GS, Palatinus JA, O’Quinn M, Yost MJ, Gourdie RG. Novel therapies for scar reduction and regenerative healing of

skin wounds. Trends Biotechnol. 2008; 26: 173-80, CrossRef.

Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. 2008; 2: 141-50, CrossRef.

Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: Mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells. 2007; 25: 2739-49, CrossRef.

Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F, et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006; 107: 367-72, CrossRef.

Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M. Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells. 2006; 24: 74-85, CrossRef.

Ashcroft GS, Yang X, Glick AB, Weinstein M, Letterio JL, Mizel DE, et al. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol. 1999; 1: 260-6, CrossRef.

Redd MJ, Cooper L, Wood W, Stramer B, Martin P. Wound healing and inflammation: embryos reveal the way to perfect repair. Philos Trans R Soc Lond B Biol Sci. 2004; 359: 777-84, CrossRef.

Brown LF, Yeo KT, Berse B, Yeo TK, Senger DR, Dvorak HF, et al. Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing. J Exp Med. 1992; 176: 1375-9, CrossRef.

Gruber R, Kandler B, Holzmann P, Vogele-Kadletz M, Losert U, Fischer MB, et al. Bone marrow stromal cells can provide a local environment that favors migration and formation of tubular structures of endothelial cells. Tissue Eng. 2005; 11: 896-903, CrossRef.

Kaigler D, Krebsbach PH, Polverini PJ, Mooney DJ. Role of vascular endothelial growth factor in bone marrow stromal cell modulation of endothelial cells. Tissue Eng. 2003; 9: 95-103, CrossRef.

Lozito TP, Taboas JM, Kuo CK, Tuan RS. Mesenchymal stem cell modification of endothelial matrix regulates their vascular differentiation. J Cell Biochem. 2009; 107: 706-13, CrossRef.

Kato J, Tsuruda T, Kita T, Kitamura K, Eto T. Adrenomedullin: a protective factor for blood vessels. Arterioscler Thromb Vasc Biol. 2005; 25: 2480-7, CrossRef.

Renault MA, Roncalli J, Tongers J, Misener S, Thorne T, Jujo K, et al. The Hedgehog transcription factor Gli3 modulates angiogenesis. Circ Res. 2009; 105: 818-26, CrossRef.

Bianco P, Robey PG, Simmons PJ. Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell. 2008; 2: 313-9, CrossRef.

Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D, Shimizu H. Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol. 2008; 180: 2581-7, CrossRef.

Fu X, Fang L, Li X, Cheng B, Sheng Z. Enhanced wound-healing quality with bone marrow mesenchymal stem cells autografting after skin injury. Wound Repair Regen. 2006; 14: 325-35, CrossRef.

Lozito TP, Kuo CK, Taboas JM, Tuan RS. Human mesenchymal stem cells express vascular cell phenotypes upon interaction with endothelial cell matrix. J Cell Biochem. 2009; 107: 714-22, CrossRef.

Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells. 2007; 25: 2648-59, CrossRef.




DOI: https://doi.org/10.18585/inabj.v8i2.191

Indexed by:

                 

                  

               

     

 

The Prodia Education and Research Institute