Sains Malaysiana 47(10)(2018):
2463–2471
http://dx.doi.org/10.17576/jsm-2018-4710-23
Epithelial to Mesenchymal Transition and Reepithelialisation in Wound Healing: A Review of Comparison
(Peralihan Epitelium
kepada Mesenkima
dan Pengepitelium Semula dalam Penyembuhan
Luka: Ulasan Perbandingan)
ABID
NORDIN1,
SHIPLU
ROY
CHOWDHURY2,
AMINUDDIN
BIN SAIM3 & RUSZYMAH
BT HJ IDRUS1*
1Department of Physiology, Faculty of Medicine,
Universiti Kebangsaan
Malaysia, Jalan Yaacob
Latif, Bandar Tun Razak,
56000 Cheras, Kuala Lumpur, Federal
Territory, Malaysia
2Tissue Engineering Centre,Faculty
of Medicine, Universiti Kebangsaan
Malaysia, Jalan Yaacob
Latif, Bandar Tun Razak,
56000 Cheras, Kuala Lumpur, Federal
Territory, Malaysia
3Ear, Nose & Throat Consultant
Clinic, Ampang Puteri
Specialist Hospital, 68000 Ampang, Selangor
Darul Ehsan, Malaysia
Received:
30 March 2018/Accepted: 20 June 2018
ABSTRACT
Skin wound healing is
a complex physiological event, involving many cellular and molecular
components. The event of wound healing is the coordinated overlap
of a number of distinct phases, namely haemostasis,
inflammatory, proliferative and remodelling.
The molecular events surrounding wound healing, particularly the
reepithelialisation, has been
reported to be similar to the epithelial to mesenchymal transition
(EMT).
In this review, the mechanism between epithelialisation
and EMT were compared. Both are characterised
by the loss of epithelial integrity and increased motility. In
terms of the signalling kinases, Smad and mitogen-activated
protein kinase (MAPK) has been reported to be
involved in both reepithelialisation
and EMT.
At the transcriptional level, SLUG transcription factor has
been reported to be important for both reepithelialisation
and EMT. Extracellular matrix proteins that have been associated
with both events are collagen and laminin. Lastly, both events
required the interplay between matrix metalloproteinases (MMPs)
and its inhibitor. As a conclusion, both reepithelialisation
and EMT shares similar signaling cascade and transcriptional
regulation to exhibit decreased epithelial traits and increased
motility in keratinocytes.
Keywords: Epithelial
to mesenchymal transition; reepithelialisation;
wound healing
ABSTRAK
Penyembuhan luka ialah proses
fisiologi yang kompleks
dan melibatkan
pelbagai komponen sel dan molekul. Proses penyembuhan
luka terdiri daripada tindihan beberapa fasa yang tersusun iaitu haemostasis, inflamasi, proliferasi dan pembentukan semula tisu. Proses molekul
penyembuhan luka, khasnya pengepitelium
semula, telah
dilaporkan mempunyai persamaan dengan proses molekul
yang terlibat dalam peralihan epitelium kepada mesenkima (EMT). Dalam
kajian ini,
persamaan proses molekul antara
pengepitelium
semula dan EMT dibincangkan. Penunjuk utama untuk kedua-dua
proses ialah kehilangan
keutuhan sel epitelium yang membawa kepada
migrasi sel. Dua protein kinase
telah dilaporkan sama-sama terlibat dalam pengepitelium
semula dan EMT,
Smad dan MAPK (mitogen-activated
protein kinase). Pada tahap
transkripsi genetik,
faktor transkripsi SLUG
dilaporkan diperlukan
dalam kedua-dua
proses. Matriks ekstrasel laminin dan kolagen juga dikaitkan dengan kedua-dua proses. Akhir sekali, keseimbangan antara enzim pencerna
matriks ekstrasel
dan perencatnya juga penting dalam proses pengepitelium
semula dan EMT. Kesimpulannya,
proses epitelium semula dan EMT berkongsi
proses kawal atur
yang sama di peringkat
kinase dan faktor
transkripsi yang membolehkan mobiliti sel dan
pengurangan sifat
epitelium untuk keratinosit.
Kata kunci: Pengepitelium
semula; penyembuhan
luka; peralihan epitelium kepada mesenkima
REFERENCES
Abreu-Blanco, M.T., Watts, J.J., Verboon,
J.M. & Parkhurst, S.M. 2012. Cytoskeleton
responses in wound repair. Cellular and Molecular Life Sciences
69(15): 2469-2483.
Barrientos, S., Brem, H., Stojadinovic, O. & Tomic-Canic,
M. 2014. Clinical application of growth factors and cytokines
in wound healing. Wound Repair and Regeneration 22(5):
569-578.
Beer, H.D., Gassmann, M.G., Munz, B., Steiling, H., Engelhardt, F., Bleuel, K. & Werner, S. 2000. Expression
and function of keratinocyte growth factor and activin
in skin morphogenesis and cutaneous wound repair. Journal
of Investigative Dermatology Symposium Proceedings 5(1): 34-39.
Bhora, F.Y., Dunkin, B.J., Batzri, S., Aly,
H.M., Bass, B.L., Sidawy, A.N. &
Harmon, J.W. 1995. Effect of growth factors on cell proliferation
and epithelialization in human skin. Journal of Surgical
Research 59(2): 236-244.
Bielefeld, K.A., Amini-Nik, S. & Alman, B.A. 2013. Cutaneous
wound healing: Recruiting developmental pathways for regeneration.
Cellular and Molecular Life Sciences 70(12): 2059-2081.
Burr, S. & Penzer, R. 2005. Promoting skin health. Nursing Standard
19(36): 57-65.
Byun, J.S. & Gardner, K. 2013. Wounds
that will not heal: Pervasive cellular reprogramming in cancer.
American Journal of Pathology 182(4): 1055-1064.
Caley, M.P., Martins, V.L.C. & O’Toole, E.A. 2015. Metalloproteinases and wound healing. Advances
in Wound Care 4(4): 225-234.
Chen, K.S., Shi, M.D., Chien, C.S. &
Shih, Y.W. 2014. Pinocembrin suppresses TGF-beta1-induced
epithelial-mesenchymal transition and metastasis of human Y-79
retinoblastoma cells through inactivating alphavbeta3 integrin/FAK/p38alpha
signaling pathway. Cell Bioscience 4: 41.
Chen, M.J., Shih, S.C., Wang, H.Y., Lin, C.C., Liu, C.Y., Wang, T.E.,
Chu, C.H. & Chen, Y.J. 2013a. Caffeic
acid phenethyl ester inhibits epithelial-mesenchymal
transition of human pancreatic cancer cells. Evidence-Based
Complementary and Alternative Medicine 2013: 270906.
Chen,
Q.K., Lee, K., Radisky, D.C. & Nelson,
C.M. 2013b. Extracellular matrix proteins regulate epithelial-mesenchymal
transition in mammary epithelial cells. Differentiation 86(3): 126-132.
Cheng,
F., Shen, Y., Mohanasundaram, P., Lindström,
M., Ivaska, J., Ny,
T. & Eriksson, J.E. 2016. Vimentin coordinates fibroblast
proliferation and keratinocyte differentiation in wound healing
via TGF-β–Slug signaling. Proceedings of the National
Academy of Sciences 113(30): E4320-E4327.
Clark,
R.A.F., Folkvord, J.M. & Wertz,
R.L. 1985. Fibronectin,
as well as other extracelllular matrix
proteins, mediate human keratinocyte adherence. Journal of
Investigative Dermatology 84(5): 378-383.
Crowe,
M.J., Doetschman, T. & Greenhalgh,
D.G. 2000. Delayed wound healing in immunodeficient TGF-β1 knockout mice. Journal
of Investigative Dermatology 115(1): 3-11.
Derynck,
R. & Zhang, Y.E. 2003. Smad-dependent and Smad-independent pathways
in TGF-β family signalling.
Nature 425(6958): 577-584.
Dvorak,
H.F. 1986. Tumors: Wounds that do not heal. The New England
Journal of Medicine 315(26): 1650-1659.
Eming,
S.A., Krieg, T. & Davidson, J.M. 2007. Inflammation in
wound repair: Molecular and cellular mechanisms. Journal of
Investigative Dermatology 127(3): 514-525.
Frankowski, H.,
Gu, Y.H., Heo, J.H., Milner, R. & Del Zoppo,
G.J. 2012. Use of gel zymography
to examine matrix metalloproteinase (gelatinase) expression in
brain tissue or in primary glial cultures. Methods in
Molecular Biology 814: 221-233.
Fuchs,
E. & Cleveland, D.W. 1998. A structural
scaffolding of intermediate filaments in health and disease.
Science 279: 514-519.
Gheldof,
A. & Berx, G. 2013. Cadherins and epithelial-to-mesenchymal
transition. Progress in Molecular Biology and Translational
Science 116: 317-336.
Gialeli,
C., Theocharis, A.D. & Karamanos,
N.K. 2011. Roles of matrix metalloproteinases
in cancer progression and their pharmacological targeting.
Federation of European Biochemical Societies Journal 278(1):
16-27.
Gniadecki, R.
1998. Regulation of keratinocyte proliferation.
General Pharmacology: The Vascular System 30(5): 619-622.
Haensel,
D. & Dai, X. 2018. Epithelial-to-mesenchymal transition in
cutaneous wound healing: Where we are and where we are heading.
Developmental Dynamics 247(3): 473-480.
Hay,
E.D. 1995. An overview of epithelio-mesenchymal
transformation. Cells Tissues Organs 154(1): 8-20.
Hudson,
L.G., Newkirk, K.M., Chandler, H.L., Choi, C., Fossey,
S.L., Parent, A.E. & Kusewitt, D.F.
2009. Cutaneous
wound reepithelialization is compromised
in mice lacking functional Slug (Snai2). Journal of Dermatological
Science 56(1): 19-26.
Idrus,
R.H.B., Rameli, M.A.B., Low, K.C., Law,
J.X., Chua, K.H., Latiff, M.B.A. &
Saim, A.B. 2014. Full-thickness skin wound healing using autologous
keratinocytes and dermal fibroblasts with fibrin. Advances
in Skin & Wound Care 27(4): 171-180.
Ivaska, J.
2011. Vimentin. Central
hub in EMT induction? Small GTPases
2(1): 51-53.
Janda, E.,
Lehmann, K., Killisch, I., Jechlinger,
M., Herzig, M., Downward, J., Beug,
H. & Grünert, S. 2002. Ras
and TGFβ cooperatively regulate epithelial cell plasticity
and metastasis: Dissection of Ras signaling
pathways. Journal of Cell Biology 156(2): 299-313.
Jones,
J.C.R., Dehart, G.W., Gonzales, M. & Goldfinger,
L.E. 2000. Laminins: An overview. Microscopy Research and Technique
51(3): 211-213.
Jost,
M., Huggett, T.M., Kari, C. & Rodeck,
U. 2001. Matrix-independent survival of human keratinocytes through an EGF
receptor/MAPK-kinase-dependent pathway. Molecular Biology
of the Cell 12(5): 1519-1527.
Kalluri,
R. & Neilson, E.G. 2003. Epithelial-mesenchymal
transition and its implications for fibrosis. Journal
of Clinical Investigation 112(12): 1776-1784.
Kalluri,
R. & Weinberg, R. 2009. Review series the basics of epithelial-mesenchymal
transition. Journal of Clinical Investigation 119(6): 1420-1428.
Kao,
H.F., Chang-Chien, P.W., Chang, W.T.,
Yeh, T.M. & Wang, J.Y. 2013. Propolis inhibits TGF-β1-induced epithelial-mesenchymal
transition in human alveolar epithelial cells via PPARγ activation. International Immunopharmacology
15(3): 565-574.
Koh,
T.J. & DiPietro, L.A. 2011. Inflammation
and wound healing: The role of the macrophage. Expert Reviews
in Molecular Medicine 13: e23.
Kusewitt,
D.F., Choi, C., Newkirk, K.M., Leroy, P., Li, Y., Chavez, M.G.
& Hudson, L.G. 2009. Slug/Snai2 is a downstream mediator of epidermal growth
factor receptor-stimulated reepithelialization.
Journal of Investigative Dermatology 129(2): 491-495.
Lamouille,
S., Xu, J. & Derynck, R. 2014. Molecular mechanisms of epithelial-mesenchymal transition.
National Review Molecular Cell Biology 15(3): 178–196.
Landén,
N.X., Li, D. & Ståhle, M. 2016. Transition
from inflammation to proliferation: A critical step during wound
healing. Cellular and Molecular Life Sciences 73(20): 3861-3885.
Laurens,
N., Koolwijk, P. & De Maat, M.P.M.
2006. Fibrin structure and wound healing. Journal of Thrombosis
and Haemostasis 4(5): 932-939.
Law,
J.X., Chowdhury, S.R., Aminuddin, B.S.
& Ruszymah, B.H.I. 2017. Role of plasma-derived
fibrin on keratinocyte and fibroblast wound healing. Cell and
Tissue Banking 18(4): 585-595.
Lee,
D.Y. & Cho, K.H. 2005. The effects of epidermal
keratinocytes and dermal fibroblasts on the formation of cutaneous
basement membrane in three-dimensional culture systems.
Archives of Dermatological Research 296(7): 296-302.
Leopold,
P.L., Vincent, J. & Wang, H. 2012. A comparison of epithelial-to-mesenchymal transition and re-epithelialization.
Seminars in Cancer Biology 22(5-6): 471-483.
Li,
L., Hartley, R., Reiss, B., Sun, Y., Pu, J., Wu, D., Lin, F.,
Hoang, T., Yamada, S., Jiang, J. & Zhao, M. 2012. E-cadherin plays
an essential role in collective directional migration of large
epithelial sheets. Cellular and Molecular Life Sciences 69(16):
2779-2789.
Lu,
P., Takai, K., Weaver, V.M. & Werb,
Z. 2011. Extracellular matrix degradation
and remodeling in development and disease. Cold Spring
Harbor Perspectives in Biology 3(12): 1-24.
Maarof,
M., Law, J.X., Chowdhury, S.R., Khairoji,
K.A., Saim, A.B. & Idrus, R.B.H. 2016. Secretion of wound healing mediators by single and bi-layer skin substitutes.
Cytotechnology 68(5):
1873-1884.
Mazlyzam,
A.L., Aminuddin, B.S., Fuzina,
N.H., Norhayati, M.M., Fauziah,
O., Isa, M.R., Saim, L. & Ruszymah,
B.H.I. 2007. Reconstruction of living bilayer human skin equivalent utilizing human fibrin as a scaffold. Burns: Journal of the International Society for Burn Injuries
33(3): 355-363.
Minutti, C.M., Knipper, J.A., Allen, J.E. &
Zaiss, D.M.W. 2017. Tissue-specific contribution of macrophages to wound healing.
Seminars in Cell & Developmental Biology 61: 3-11.
Moll, I., Houdek, P., Schäfer, S., Nuber, U. & Moll,
R. 1999. Diversity of desmosomal proteins in regenerating epidermis: Immunohistochemical study using a human skin organ culture
model. Archives of Dermatological Research 291(7- 8): 437-446.
Monsuur, H.N., Boink,
M.A., Weijers, E.M., Roffel,
S., Breetveld, M., Gefen,
A., van den Broek, L.J. & Gibbs,
S. 2016. Methods to study differences in cell mobility during
skin wound healing in vitro. Journal of Biomechanics
49(8): 1381-1387.
Moreno-Bueno, G., Peinado, H., Molina,
P., Olmeda, D., Cubillo,
E., Santos, V., Palacios, J., Portillo, F. & Cano, A. 2009. The morphological and molecular features of the
epithelial-to-mesenchymal transition. Nature Protocols
4(11): 1591-1613.
Muller, M., Trocme, C., Lardy, B., Morel,
F., Halimi, S. & Benhamou,
P.Y. 2008. Matrix metalloproteinases and diabetic
foot ulcers: The ratio of MMP-1 to TIMP-1 is a predictor of wound
healing. Diabetic Medicine 25(4): 419-426.
Nordin, A., Sainik,
N.Q.A.V., Zulfarina, M.S., Naina-Mohamed,
I., Saim, A. & Bt Hj Idrus,
R. 2017. Honey and epithelial to mesenchymal transition in wound
healing: An evidence-based review. Wound Medicine 18: 8-20.
O’Kane, D., Jackson, M.V., Kissenpfennig,
A., Spence, S., Damkat-Thomas, L., Tolland,
J.P., Smyth, A.E., Denton, C.P., Elborn,
J.S., McAuley, D.F. & O’Kane, C.M. 2014. SMAD inhibition attenuates epithelial to mesenchymal transition
by primary keratinocytes in vitro. Experimental Dermatology
23(7): 497-503.
O’Toole, E.A. 2001. Extracellular matrix and keratinocyte migration. Clinical
and Experimental Dermatology 26(6): 525-530.
Odland, G. & Ross, R. 1968. Human
wound repair I . Epidermal
regeneration. The Journal of Cell Biology 39(1):
135-151.
Okada, H., Danoff, T.M., Kalluri, R., Neilson, E.G., Danoff,
T.M. & Neilson, E.G. 1997. Early
role of Fsp1 in epithelial-mesenchymal transformation.
The American Physiological Society 273(4): F563-F574.
Pastar, I., Stojadinovic,
O., Yin, N.C., Ramirez, H., Nusbaum,
A.G., Sawaya, A., Patel, S.B., Khalid, L., Isseroff,
R.R. & Tomic-Canic,
M. 2014. Epithelialization in wound healing: A comprehensive review.
Advances in Wound Care 3(7): 445-464.
Puolakkainen, P.A., Reed, M.J., Gombotz, W.R., Twardzik, D.R., Abrass, I.B. &
Helene Sage, E. 1995. Acceleration of wound
healing in aged rats by topical application of transforming growth
factor-beta1. Wound Repair and Regeneration 3(3): 330-339.
Ricard-Blum, S. 2011. The collagen family. Cold Spring Harbor Perspectives in
Biology 3(1): a004978.
Savagner, P., Kusewitt, D.F., Carver, E.A., Magnino, F., Choi, C., Gridley, T. & Hudson, L.G. 2005. Developmental transcription factor slug is required for effective
re-epithelialization by adult keratinocytes. Journal of Cellular
Physiology 202(3): 858-866.
Singer, A.J. & Clark, R.A.F. 1999. Cutaneous wound healing. The New England Journal of Medicine
341(10): 738-746.
Soo, C., Shaw, W.W., Zhang, X., Longaker,
M.T., Howard, E.W. & Ting, K. 2000. Differential expression
of matrix metalloproteinases and their tissue-derived inhibitors
in cutaneous wound repair. Plastic and Reconstructive Surgery
105(2): 638-647.
Szpaderska, A.M., Egozi,
E.I., Gamelli, R.L. & DiPietro,
L.A. 2003. The effect of thrombocytopenia on
dermal wound healing. The Journal of Investigative Dermatology
120(6): 1130-1137.
Tonnesen, M.G., Feng, X. & Clark, R.A. 2000. Angiogenesis in wound healing. The Journal of Investigative Dermatology. Symposium
Proceedings 5(1): 40-46.
Tracy, L.E., Minasian, R.A. & Caterson, E.J. 2016. Extracellular
matrix and dermal fibroblast function in the healing wound. Advances
in Wound Care 5(3): 119-136.
Tseng, J., Lin, C., Su, L., Fu, H., Yang, S. & Chuu, C. 2016. CAPE
suppresses migration and invasion of prostate cancer cells via
activation of non-canonical Wnt signaling.
Oncotarget 7(25): 38010-38024.
Velnar, T., Bailey, T. & Smrkolj, V. 2009. The wound healing process: An overview of the cellular and molecular
mechanisms. Journal of International Medical Research 37(5):
1528-1542.
Vićovac, L. & Aplin, J.D. 1996. Epithelial-mesenchymal transition during trophoblast
differentiation. Acta
Anatomica 156(3): 202-216.
Werner, S. & Grose, R. 2003. Regulation of wound healing by growth factors and cytokines.
Physiological Reviews 83(3): 835-870.
Xu, J., Lamouille, S. & Derynck, R. 2009. TGF-beta-induced epithelial to mesenchymal transition. Cell
Research 19(2): 156-172.
Xue, M. & Jackson, C.J. 2015. Extracellular matrix reorganization during wound healing and its impact
on abnormal scarring. Advances in Wound Care 4(3):
119-136.
Yalcinkaya, E., Celik, M. & Bugan, B. 2014. Extracellular
matrix turnover: A balance between MMPs and their inhibitors.
Arquivos Brasileiros de
Cardiologia 102(5): 519-520.
Yau, J.W., Teoh, H. & Verma, S. 2015. Endothelial cell control
of thrombosis. BMC Cardiovascular Disorders 15:
130.
Zeisberg, M., Maeshima, Y., Mosterman,
B. & Kalluri, R. 2002. Renal fibrosis. The American Journal
of Pathology 160(6): 2001-2008.
Zeisberg, M. & Neilson, E.G. 2009. Review
series personal perspective biomarkers for epithelial-mesenchymal
transitions. The Journal of Clinical Investigation 119(6):
1429-1437.
*Corresponding author; email:
ruszyidrus@gmail.com