1. Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Sciences, General Hospital of PLA, Beijing 100853, China; 2. Burns Institute, the First Affiliated Hospital, General Hospital of PLA, Trauma Center of Postgraduate Medical College, Beijing 100048, China; 3. Thoracic and Cardiovascular Surgery Department, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
Umbilical cord mesenchymal stem cells (MSCs) are a unique, accessible, and non-controversial source of early stem cells that can be readily manipulated. As the most common pluripotent cell, bone marrow-derived MSCs display limitations with the progress of stem cell therapy. By contrast, umbilical cord-derived cells, which have plentiful resources, are more accessible. However, several uncertain aspects, such as the effect of donor selection or culture conditions, long-term therapeutic effects, product consistency, and potential tumorigenicity, are the bottleneck in this clinical therapy. MSCs are predicted to undergo an unprecedented development in clinical treatment when a generally acknowledged criterion emerges. In the current paper, we highlight the application of umbilical cord-derived MSCs in skin therapies based on our previous studies, as well as the achievements of our peers in this field. This paper focuses on the strategies, challenges, and potential of this novel therapy.
Easy to obtain. No harm to the donor. Can be used in several people
BMMSC
Bone marrow
Mesoblast
CD73, CD44CD105, CD90
CD45,CD34,
Low
High
Safe
Low
Low
Not easy to obtain. Can harm the donor
UCBMSC
Umbilical cord blood
Mesoblast
CD73, CD44CD105, CD90
CD45,CD34
No
High
Safe
Low
Lower
Easy to obtain. No harm to the donor. Just for one child
Tab.1
1
Can A, Karahuseyinoglu S. Concise review: human umbilical cord stroma with regard to the source of fetus-derived stem cells. Stem Cells 2007; 25(11): 2886-2895 doi: 10.1634/stemcells.2007-0417 pmid:17690177
2
Raio L, Ghezzi F, Di Naro E, Gomez R, Franchi M, Mazor M, Brühwiler H. Sonographic measurement of the umbilical cord and fetal anthropometric parameters. Eur J Obstet Gynecol Reprod Biol 1999; 83(2): 131-135 doi: 10.1016/S0301-2115(98)00314-5 pmid:10391521
3
Di Naro E, Ghezzi F, Raio L, Franchi M, D’Addario V. Umbilical cord morphology and pregnancy outcome. Eur J Obstet Gynecol Reprod Biol 2001; 96(2): 150-157 doi: 10.1016/S0301-2115(00)00470-X pmid:11384798
4
Copland IB, Adamson SL, Post M, Lye SJ, Caniggia I. TGF-beta 3 expression during umbilical cord development and its alteration in pre-eclampsia. Placenta 2002; 23(4): 311-321 doi: 10.1053/plac.2001.0778 pmid:11969342
5
Mizoguchi M, Suga Y, Sanmano B, Ikeda S, Ogawa H. Organotypic culture and surface plantation using umbilical cord epithelial cells: morphogenesis and expression of differentiation markers mimicking cutaneous epidermis. J Dermatol Sci 2004; 35(3): 199-206 doi: 10.1016/j.jdermsci.2004.06.003 pmid:15381241
6
Sanmano B, Mizoguchi M, Suga Y, Ikeda S, Ogawa H. Engraftment of umbilical cord epithelial cells in athymic mice: in an attempt to improve reconstructed skin equivalents used as epithelial composite. J Dermatol Sci 2005; 37(1): 29-39 doi: 10.1016/j.jdermsci.2004.10.008 pmid:15619432
Karahuseyinoglu S, Cinar O, Kilic E, Kara F, Akay GG, Demiralp DO, Tukun A, Uckan D, Can A. Biology of stem cells in human umbilical cord stroma: in situ and in vitro surveys. Stem Cells 2007; 25(2): 319-331 doi: 10.1634/stemcells.2006-0286 pmid:17053211
10
Bieback K, Kern S, Klüter H, Eichler H. Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells 2004; 22(4): 625-634 doi: 10.1634/stemcells.22-4-625 pmid:15277708
11
Kern S, Eichler H, Stoeve J, Klüter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 2006; 24(5): 1294-1301 doi: 10.1634/stemcells.2005-0342 pmid:16410387
12
Baksh D, Yao R, Tuan RS. Comparison of proliferative and multilineage differentiation potential of human mesenchymal stem cells derived from umbilical cord and bone marrow. Stem Cells 2007; 25(6): 1384-1392 doi: 10.1634/stemcells.2006-0709 pmid:17332507
13
Lund RD, Wang S, Lu B, Girman S, Holmes T, Sauvé Y, Messina DJ, Harris IR, Kihm AJ, Harmon AM, Chin FY, Gosiewska A, Mistry SK. Cells isolated from umbilical cord tissue rescue photoreceptors and visual functions in a rodent model of retinal disease. Stem Cells 2007; 25(3): 602-611 doi: 10.1634/stemcells.2006-0308 pmid:17053209
14
Gao L, Chen X, Zhang X, Liu Y, Kong P, Peng X, Liu L, Liu H, Zeng D. Human umbilical cord blood-derived stromal cell, a new resource of feeder layer to expand human umbilical cord blood CD34+ cells in vitro. Blood Cells Mol Dis 2006; 36(2): 322-328 doi: 10.1016/j.bcmd.2005.12.036 pmid:16500123
15
Wang JF, Wang LJ, Wu YF, Xiang Y, Xie CG, Jia BB, Harrington J, McNiece IK. Mesenchymal stem/progenitor cells in human umbilical cord blood as support for ex vivo expansion of CD34(+) hematopoietic stem cells and for chondrogenic differentiation. Haematologica 2004; 89(7): 837-844 pmid:15257936
16
Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I, Fisk NM. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 2001; 98(8): 2396-2402 doi: 10.1182/blood.V98.8.2396 pmid:11588036
17
Lu LL, Liu YJ, Yang SG, Zhao QJ, Wang X, Gong W, Han ZB, Xu ZS, Lu YX, Liu D, Chen ZZ, Han ZC. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica 2006; 91(8): 1017-1026 pmid:16870554
18
Sarugaser R, Lickorish D, Baksh D, Hosseini MM, Davies JE. Human umbilical cord perivascular (HUCPV) cells: a source of mesenchymal progenitors. Stem Cells 2005; 23(2): 220-229 doi: 10.1634/stemcells.2004-0166 pmid:15671145
19
Fu YS, Shih YT, Cheng YC, Min MY. Transformation of human umbilical mesenchymal cells into neurons in vitro. J Biomed Sci 2004; 11(5): 652-660 doi: 10.1007/BF02256131 pmid:15316141
20
Wang HS, Hung SC, Peng ST, Huang CC, Wei HM, Guo YJ, Fu YS, Lai MC, Chen CC. Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord. Stem Cells 2004; 22(7): 1330-1337 doi: 10.1634/stemcells.2004-0013 pmid:15579650
21
Conconi MT, Burra P, Di Liddo R, Calore C, Turetta M, Bellini S, Bo P, Nussdorfer GG, Parnigotto PP. CD105(+) cells from Wharton’s jelly show in vitro and in vivo myogenic differentiative potential. Int J Mol Med 2006; 18(6): 1089-1096 pmid:17089012
22
Wu KH, Zhou B, Lu SH, Feng B, Yang SG, Du WT, Gu DS, Han ZC, Liu YL. In vitro and in vivo differentiation of human umbilical cord derived stem cells into endothelial cells. J Cell Biochem 2007; 100(3): 608-616 doi: 10.1002/jcb.21078 pmid:16960877
23
Xu HH, Zhao L, Detamore MS, Takagi S, Chow LC. Umbilical cord stem cell seeding on fast-resorbable calcium phosphate bone cement. Tissue Eng Part A 2010; 16(9): 2743-2753 doi: 10.1089/ten.tea.2009.0757 pmid:20388037
24
Caballero M, Reed CR, Madan G, van Aalst JA. Osteoinduction in umbilical cord- and palate periosteum-derived mesenchymal stem cells. Ann Plast Surg 2010; 64(5): 605-609 pmid:20395805
25
Schneider RK, Püllen A, Kramann R, Bornemann J, Knüchel R, Neuss S, Perez-Bouza A. Long-term survival and characterisation of human umbilical cord-derived mesenchymal stem cells on dermal equivalents. Differentiation 2010; 79(3): 182-193 doi: 10.1016/j.diff.2010.01.005 pmid:20153102
26
Alaminos M, Pérez-K?hler B, Garzón I, García-Honduvilla N, Romero B, Campos A, Buján J. Transdifferentiation potentiality of human Wharton’s jelly stem cells towards vascular endothelial cells. J Cell Physiol 2010; 223(3): 640-647 pmid:20143331
27
Anzalone R, Lo Iacono M, Corrao S, Magno F, Loria T, Cappello F, Zummo G, Farina F, La Rocca G. New emerging potentials for human Wharton’s jelly mesenchymal stem cells: immunological features and hepatocyte-like differentiative capacity. Stem Cells Dev 2010; 19(4): 423-438 doi: 10.1089/scd.2009.0299 pmid:19958166
28
Zhang HT, Fan J, Cai YQ, Zhao SJ, Xue S, Lin JH, Jiang XD, Xu RX. Human Wharton’s jelly cells can be induced to differentiate into growth factor-secreting oligodendrocyte progenitor-like cells. Differentiation 2010; 79(1): 15-20 doi: 10.1016/j.diff.2009.09.002 pmid:19800163
29
Bailey MM, Wang L, Bode CJ, Mitchell KE, Detamore MS. A comparison of human umbilical cord matrix stem cells and temporomandibular joint condylar chondrocytes for tissue engineering temporomandibular joint condylar cartilage. Tissue Eng 2007; 13(8): 2003-2010 doi: 10.1089/ten.2006.0150 pmid:17518722
30
Ma L, Feng XY, Cui BL, Law F, Jiang XW, Yang LY, Xie QD, Huang TH. Human umbilical cord Wharton’s jelly-derived mesenchymal stem cells differentiation into nerve-like cells. Chin Med J (Engl) 2005; 118(23): 1987-1993 pmid:16336835
31
Li YS, Milner PG, Chauhan AK, Watson MA, Hoffman RM, Kodner CM, Milbrandt J, Deuel TF. Cloning and expression of a developmentally regulated protein that induces mitogenic and neurite outgrowth activity. Science 1990; 250(4988): 1690-1694 doi: 2270483" target="_blank">10.1126/science. pmid:2270483 pmid:2270483
32
Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, Phinney DG. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA 2003;100:8407-8411
33
Rojas M, Xu J, Woods CR, Mora AL, Spears W, Roman J, Brigham KL. Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol 2005; 33(2): 145-152 doi: 10.1165/rcmb.2004-0330OC pmid:15891110
34
T?gel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 2005; 289(1): F31-F42 doi: 10.1152/ajprenal.00007.2005 pmid:15713913
35
Togel F, Weiss K, Yang Y, Hu Z, Zhang P, Westenfelder C. Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury. Am J Physiol Renal Physiol 2007;292(5):F1626-F1635
36
Carlson S, Trial J, Soeller C, Entman ML. Cardiac mesenchymal stem cells contribute to scar formation after myocardial infarction. Cardiovasc Res 2011; 91(1): 99-107 doi: 10.1093/cvr/cvr061 pmid:21357194
37
Amado LC, Saliaris AP, Schuleri KH, St John M, Xie JS, Cattaneo S, Durand DJ, Fitton T, Kuang JQ, Stewart G, Lehrke S, Baumgartner WW, Martin BJ, Heldman AW, Hare JM. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc Natl Acad Sci USA 2005;102:11474-11479
38
Miyahara Y, Nagaya N, Kataoka M, Yanagawa B, Tanaka K, Hao H, Ishino K, Ishida H, Shimizu T, Kangawa K, Sano S, Okano T, Kitamura S, Mori H.Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nat Med 2006;12:459-465
39
Fiorina P, Jurewicz M, Augello A, Vergani A, Dada S, La Rosa S, Selig M, Godwin J, Law K, Placidi C, Smith RN, Capella C, Rodig S, Adra CN, Atkinson M, Sayegh MH, Abdi R. Immunomodulatory function of bone marrow-derived mesenchymal stem cells in experimental autoimmune type 1 diabetes. J Immunol 2009;183:993-1004
Tang YL, Zhao Q, Zhang YC, Cheng L, Liu M, Shi J, Yang YZ, Pan C, Ge J, Phillips MI. Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium. Regul Pept 2004; 117(1): 3-10 doi: 10.1016/j.regpep.2003.09.005 pmid:14687695
42
Herrera MB, Bussolati B, Bruno S, Fonsato V, Romanazzi GM, Camussi G. Mesenchymal stem cells contribute to the renal repair of acute tubular epithelial injury. Int J Mol Med 2004; 14(6): 1035-1041 pmid:15547670
43
Prasanna SJ, Gopalakrishnan D, Shankar SR, Vasandan AB. Pro-inflammatory cytokines, IFNγ and TNFα, influence immune properties of human bone marrow and Wharton jelly mesenchymal stem cells differentially. PLoS ONE 2010; 5(2): e9016 doi: 10.1371/journal.pone.0009016 pmid:20126406
44
Lazarus H, Haynesworth S, Gerson S, Rosenthal N, Caplan A. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant 1995; 16:557-564
45
Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M, Sussman M, Orchard P, Marx JC, Pyeritz RE, Brenner MK. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 1999; 5:309-313
46
Liechty KW, MacKenzie TC, Shaaban AF, Radu A, Moseley AM, Deans R, Marshak DR, Flake AW. Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nat Med 2000; 6(11): 1282-1286 doi: 10.1038/81395 pmid:11062543
47
Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, Hardy W, Devine S, Ucker D, Deans R, Moseley A, Hoffman R. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 2002; 30(1): 42-48 doi: 10.1016/S0301-472X(01)00769-X pmid:11823036
48
Shaw TJ, Martin P. Wound repair at a glance. J Cell Sci 2009; 122(Pt 18): 3209-3213 doi: 10.1242/jcs.031187 pmid:19726630
49
Fathke C, Wilson L, Hutter J, Kapoor V, Smith A, Hocking A, Isik F. Contribution of bone marrow-derived cells to skin: collagen deposition and wound repair. Stem Cells 2004; 22(5): 812-822 doi: 10.1634/stemcells.22-5-812 pmid:15342945
50
Neuss S, Schneider RK, Tietze L, Knüchel R, Jahnen-Dechent W. Secretion of fibrinolytic enzymes facilitates human mesenchymal stem cell invasion into fibrin clots. Cells Tissues Organs 2010; 191(1): 36-46 doi: 10.1159/000215579 pmid:19390164
51
Halkos ME, Zhao ZQ, Kerendi F, Wang NP, Jiang R, Schmarkey LS, Martin BJ, Quyyumi AA, Few WL, Kin H, Guyton RA, Vinten-Johansen J. Intravenous infusion of mesenchymal stem cells enhances regional perfusion and improves ventricular function in a porcine model of myocardial infarction. Basic Res Cardiol 2008; 103(6): 525-536 doi: 10.1007/s00395-008-0741-0 pmid:18704259
52
Nakagawa H, Akita S, Fukui M, Fujii T, Akino K. Human mesenchymal stem cells successfully improve skin-substitute wound healing. Br J Dermatol 2005; 153(1): 29-36 doi: 10.1111/j.1365-2133.2005.06554.x pmid:16029323
53
Carlin R, Davis D, Weiss M, Schultz B, Troyer D. Expression of early transcription factors Oct-4, Sox-2 and Nanog by porcine umbilical cord (PUC) matrix cells. Reprod Biol Endocrinol 2006 4:8 doi: 10.1186/1477-7827-4-8 pmid:16460563
54
Sheng Z, Fu X, Cai S, Lei Y, Sun T, Bai X, Chen M. Regeneration of functional sweat gland-like structures by transplanted differentiated bone marrow mesenchymal stem cells. Wound Repair Regen 2009; 17(3): 427-435 doi: 10.1111/j.1524-475X.2009.00474.x pmid:19660052
55
Xu Y, Huang S, Ma K, Fu X, Han W, Sheng Z. Promising new potential for mesenchymal stem cells derived from human umbilical cord Wharton’s jelly: sweat gland cell-like differentiative capacity. J Tissue Eng Regen Med 2011Sep13. [Epub ahead of print] doi: 10.1002/term.468 pmid:21916019
56
Tarte K, Gaillard J, Lataillade JJ, Fouillard L, Becker M, Mossafa H, Tchirkov A, Rouard H, Henry C, Splingard M, Dulong J, Monnier D, Gourmelon P, Gorin NC, Sensebé L; Société Fran?aise de Greffe de Moelle et Thérapie Cellulaire. Clinical-grade production of human mesenchymal stromal cells: occurrence of aneuploidy without transformation. Blood 2010; 115(8): 1549-1553 doi: 10.1182/blood-2009-05-219907 pmid:20032501
57
Klopp AH, Spaeth EL, Dembinski JL, Woodward WA, Munshi A, Meyn RE, Cox JD, Andreeff M, Marini FC. Tumor irradiation increases the recruitment of circulating mesenchymal stem cells into the tumor microenvironment. Cancer Res 2007; 67(24): 11687-11695 doi: 10.1158/0008-5472.CAN-07-1406 pmid:18089798
58
Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 449(7162): 557-563 doi: 10.1038/nature06188 pmid:17914389