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BMC Medicine
Published in: BMC Medicine 1/2011

Open Access 01-12-2011 | Research article

Differential properties of human ACL and MCL stem cells may be responsible for their differential healing capacity

Authors: Jianying Zhang, Tiffany Pan, Hee-Jeong Im, Freddie H Fu, James HC Wang

Published in: BMC Medicine | Issue 1/2011

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Abstract

Background

The human anterior cruciate ligament (hACL) and medial collateral ligament (hMCL) of the knee joint are frequently injured, especially in athletic settings. It has been known that, while injuries to the MCL typically heal with conservative treatment, ACL injuries usually do not heal. As adult stem cells repair injured tissues through proliferation and differentiation, we hypothesized that the hACL and hMCL contain stem cells exhibiting unique properties that could be responsible for the differential healing capacity of the two ligaments.

Methods

To test the above hypothesis, we derived ligament stem cells from normal hACL and hMCL samples from the same adult donors using tissue culture techniques and characterized their properties using immunocytochemistry, RT-PCR, and flow cytometry.

Results

We found that both hACL stem cells (hACL-SCs) and hMCL stem cells (hMCL-SCs) formed colonies in culture and expressed stem cell markers nucleostemin and stage-specific embryonic antigen-4 (SSEA-4). Moreover, both hACL-SCs and hMCL-SCs expressed CD surface markers for mesenchymal stem cells, including CD44 and CD90, but not those markers for vascular cells, CD31, CD34, CD45, and CD146. However, hACL-SCs differed from hMCL-SCs in that the size and number of hACL-SC colonies in culture were much smaller and grew more slowly than hMCL-SC colonies. Moreover, fewer hACL-SCs in cell colonies expressed stem cell markers STRO-1 and octamer-binding transcription factor-4 (Oct-4) than hMCL-SCs. Finally, hACL-SCs had less multi-differentiation potential than hMCL-SCs, evidenced by differing extents of adipogenesis, chondrogenesis, and osteogenesis in the respective induction media.

Conclusions

This study shows for the first time that hACL-SCs are intrinsically different from hMCL-SCs. We suggest that the differences in their properties contribute to the known disparity in healing capabilities between the two ligaments.
Appendix
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Literature
1.
Frank CB, Jackson DW: The science of reconstruction of the anterior cruciate ligament. J Bone Joint Surg Am. 1997, 79: 1556-1576.PubMed
2.
Barrack RL, Bruckner JD, Kneisl J, Inman WS, Alexander AH: The outcome of nonoperatively treated complete tears of the anterior cruciate ligament in active young adults. Clin Orthop Relat Res. 1990, 259: 192-199.PubMed
3.
Woo SL, Niyibizi C, Matyas J, Kavalkovich K, Weaver-Green C, Fox RJ: Medial collateral knee ligament healing. Combined medial collateral and anterior cruciate ligament injuries studied in rabbits. Acta Orthop Scand. 1997, 68: 142-148. 10.3109/17453679709003997.CrossRefPubMed
4.
Chen H, Tang Y, Li S, Shen Y, Liu X, Zhong C: Biologic characteristics of fibroblast cells cultured from the knee ligaments. Chin J Traumatol. 2002, 5: 92-96.PubMed
5.
Bedi A, Kawamura S, Ying L, Rodeo SA: Differences in tendon graft healing between the intra-articular and extra-articular ends of a bone tunnel. HSS J. 2009, 5: 51-57. 10.1007/s11420-008-9096-1.CrossRefPubMed
6.
Beynnon BD, Fleming BC, Labovitch R, Parsons B: Chronic anterior cruciate ligament deficiency is associated with increased anterior translation of the tibia during the transition from non-weightbearing to weightbearing. J Orthop Res. 2002, 20: 332-337. 10.1016/S0736-0266(01)00115-2.CrossRefPubMed
7.
Cao M, Stefanovic-Racic M, Georgescu HI, Fu FH, Evans CH: Does nitric oxide help explain the differential healing capacity of the anterior cruciate, posterior cruciate, and medial collateral ligaments?. Am J Sports Med. 2000, 28: 176-182.PubMed
8.
Bray RC, Leonard CA, Salo PT: Correlation of healing capacity with vascular response in the anterior cruciate and medial collateral ligaments of the rabbit. J Orthop Res. 2003, 21: 1118-1123. 10.1016/S0736-0266(03)00078-0.CrossRefPubMed
9.
Amiel D, Nagineni CN, Choi SH, Lee J: Intrinsic properties of ACL and MCL cells and their responses to growth factors. Med Sci Sports Exerc. 1995, 27: 844-851.CrossRefPubMed
10.
Yoshida M, Fujii K: Differences in cellular properties and responses to growth factors between human ACL and MCL cells. J Orthop Sci. 1999, 4: 293-298. 10.1007/s007760050106.CrossRefPubMed
11.
Gao J, Caplan AI: Mesenchymal stem cells and tissue engineering for orthopaedic surgery. Chir Organi Mov. 2003, 88: 305-316.PubMed
12.
Young RG, Butler DL, Weber W, Caplan AI, Gordon SL, Fink DJ: Use of mesenchymal stem cells in a collagen matrix for Achilles tendon repair. J Orthop Res. 1998, 16: 406-413. 10.1002/jor.1100160403.CrossRefPubMed
13.
Bruder SP, Fink DJ, Caplan AI: Mesenchymal stem cells in bone development, bone repair, and skeletal regeneration therapy. J Cell Biochem. 1994, 56: 283-294.CrossRefPubMed
14.
Caplan AI: The mesengenic process. Clin Plast Surg. 1994, 21: 429-435.PubMed
15.
Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH: Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001, 7: 211-228. 10.1089/107632701300062859.CrossRefPubMed
16.
Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH: Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002, 13: 4279-4295. 10.1091/mbc.E02-02-0105.CrossRefPubMedPubMedCentral
17.
Erices A, Conget P, Minguell JJ: Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol. 2000, 109: 235-242. 10.1046/j.1365-2141.2000.01986.x.CrossRefPubMed
18.
De Bari C, Dell'Accio F, Tylzanowski P, Luyten FP: Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum. 2001, 44: 1928-1942. 10.1002/1529-0131(200108)44:8<1928::AID-ART331>3.0.CO;2-P.CrossRefPubMed
19.
Risbud MV, Guttapalli A, Tsai TT, Lee JY, Danielson KG, Vaccaro AR, Albert TJ, Gazit Z, Gazit D, Shapiro IM: Evidence for skeletal progenitor cells in the degenerate human intervertebral disc. Spine. 2007, 32: 2537-2544. 10.1097/BRS.0b013e318158dea6.CrossRefPubMed
20.
Gronthos S, Mankani M, Brahim J, Robey PG, Shi S: Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci USA. 2000, 97: 13625-13630. 10.1073/pnas.240309797.CrossRefPubMedPubMedCentral
21.
Gronthos S, Mrozik K, Shi S, Bartold PM: Ovine periodontal ligament stem cells: isolation, characterization, and differentiation potential. Calcif Tissue Int. 2006, 79: 310-317. 10.1007/s00223-006-0040-4.CrossRefPubMed
22.
Bi Y, Ehirchiou D, Kilts TM, Inkson CA, Embree MC, Sonoyama W, Li L, Leet AI, Seo BM, Zhang L, Shi S, Young MF: Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat Med. 2007, 13: 1219-1227. 10.1038/nm1630.CrossRefPubMed
23.
Zhang J, Wang JH: Characterization of differential properties of rabbit tendon stem cells and tenocytes. BMC Musculoskelet Disord. 2010, 11: 10-10.1186/1471-2474-11-10.CrossRefPubMedPubMedCentral
24.
Furumatsu T, Hachioji M, Saiga K, Takata N, Yokoyama Y, Ozaki T: Anterior cruciate ligament-derived cells have high chondrogenic potential. Biochem Biophys Res Commun. 2010, 391: 1142-1147. 10.1016/j.bbrc.2009.12.044.CrossRefPubMed
25.
Normile D: Cell proliferation. Common control for cancer, stem cells. Science. 2002, 298: 1869-10.1126/science.298.5600.1869.CrossRefPubMed
26.
Tsai RY, McKay RD: A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells. Genes Dev. 2002, 16: 2991-3003. 10.1101/gad.55671.CrossRefPubMedPubMedCentral
27.
Kafienah W, Mistry S, Williams C, Hollander AP: Nucleostemin is a marker of proliferating stromal stem cells in adult human bone marrow. Stem Cells. 2006, 24: 1113-1120. 10.1634/stemcells.2005-0416.CrossRefPubMed
28.
Pesce M, Gross MK, Scholer HR: In line with our ancestors: Oct-4 and the mammalian germ.[erratum appears in Bioessays 1998 Dec;20:1056]. Bioessays. 1998, 20: 722-732. 10.1002/(SICI)1521-1878(199809)20:9<722::AID-BIES5>3.0.CO;2-I.CrossRefPubMed
29.
Niwa H, Toyooka Y, Shimosato D, Strumpf D, Takahashi K, Yagi R, Rossant J: Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation.[see comment]. Cell. 2005, 123: 917-929. 10.1016/j.cell.2005.08.040.CrossRefPubMed
30.
Hay DC, Sutherland L, Clark J, Burdon T: Oct-4 knockdown induces similar patterns of endoderm and trophoblast differentiation markers in human and mouse embryonic stem cells. Stem Cells. 2004, 22: 225-235. 10.1634/stemcells.22-2-225.CrossRefPubMed
31.
Reubinoff BE, Pera MF, Fong CY, Trounson A, Bongso A: Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol. 2000, 18: 399-404. 10.1038/74447.CrossRefPubMed
32.
Kannagi R, Cochran NA, Ishigami F, Hakomori S, Andrews PW, Knowles BB, Solter D: Stage-specific embryonic antigens (SSEA-3 and -4) are epitopes of a unique globo-series ganglioside isolated from human teratocarcinoma cells. EMBO J. 1983, 2: 2355-2361.PubMedPubMedCentral
33.
Brimble SN, Sherrer ES, Uhl EW, Wang E, Kelly S, Merrill AH, Robins AJ, Schulz TC: The cell surface glycosphingolipids SSEA-3 and SSEA-4 are not essential for human ESC pluripotency. Stem Cells. 2007, 25: 54-62. 10.1634/stemcells.2006-0232.CrossRefPubMed
34.
35.
Gang EJ, Bosnakovski D, Figueiredo CA, Visser JW, Perlingeiro RC: SSEA-4 identifies mesenchymal stem cells from bone marrow. Blood. 2007, 109: 1743-1751. 10.1182/blood-2005-11-010504.CrossRefPubMed
36.
Simmons PJ, Torok-Storb B: Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1. Blood. 1991, 78: 55-62.PubMed
37.
Gronthos S, Graves SE, Ohta S, Simmons PJ: The STRO-1+ fraction of adult human bone marrow contains the osteogenic precursors. Blood. 1994, 84: 4164-4173.PubMed
38.
Stewart K, Walsh S, Screen J, Jefferiss CM, Chainey J, Jordan GR, Beresford JN: Further characterization of cells expressing STRO-1 in cultures of adult human bone marrow stromal cells. J Bone Miner Res. 1999, 14: 1345-1356. 10.1359/jbmr.1999.14.8.1345.CrossRefPubMed
39.
Dennis JE, Carbillet JP, Caplan AI, Charbord P: The STRO-1+ marrow cell population is multipotential. Cells Tissues Organs. 2002, 170: 73-82. 10.1159/000046182.CrossRefPubMed
40.
Seo BM, Miura M, Gronthos S, Bartold PM, Batouli S, Brahim J, Young M, Robey PG, Wang CY, Shi S: Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet. 2004, 364: 149-155. 10.1016/S0140-6736(04)16627-0.CrossRefPubMed
41.
Kolf CM, Cho E, Tuan RS: Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation. Arthritis Res & Ther. 2007, 9: 204-10.1186/ar2116.CrossRef
42.
Segawa Y, Muneta T, Makino H, Nimura A, Mochizuki T, Ju YJ, Ezura Y, Umezawa A, Sekiya I: Mesenchymal stem cells derived from synovium, meniscus, anterior cruciate ligament, and articular chondrocytes share similar gene expression profiles. J Orthop Res. 2009, 27: 435-441. 10.1002/jor.20786.CrossRefPubMed
43.
Kaufman DS, Hanson ET, Lewis RL, Auerbach R, Thomson JA: Hematopoietic colony-forming cells derived from human embryonic stem cells. Proc Natl Acad Sci USA. 2001, 98: 10716-10721. 10.1073/pnas.191362598.CrossRefPubMedPubMedCentral
44.
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR: Multilineage potential of adult human mesenchymal stem cells. Science. 1999, 284: 143-147. 10.1126/science.284.5411.143.CrossRefPubMed
45.
Wexler SA, Donaldson C, Denning-Kendall P, Rice C, Bradley B, Hows JM: Adult bone marrow is a rich source of human mesenchymal 'stem' cells but umbilical cord and mobilized adult blood are not. Br J Haematol. 2003, 121: 368-374. 10.1046/j.1365-2141.2003.04284.x.CrossRefPubMed
46.
Phinney DG, Prockop DJ: Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair--current views. Stem Cells. 2007, 25: 2896-2902. 10.1634/stemcells.2007-0637.CrossRefPubMed
47.
DeLisser HM, Newman PJ, Albelda SM: Molecular and functional aspects of PECAM-1/CD31. Immunol Today. 1994, 15: 490-495. 10.1016/0167-5699(94)90195-3.CrossRefPubMed
48.
Simmons DL, Satterthwaite AB, Tenen DG, Seed B: Molecular cloning of a cDNA encoding CD34, a sialomucin of human hematopoietic stem cells. J Immunol. 1992, 148: 267-271.PubMed
49.
Salomon D, Ayalon O, Patel-King R, Hynes RO, Geiger B: Extrajunctional distribution of N-cadherin in cultured human endothelial cells. J Cell Sci. 1992, 102: 7-17.PubMed
50.
Fischer EH, Charbonneau H, Tonks NK: Protein tyrosine phosphatases: a diverse family of intracellular and transmembrane enzymes. Science. 1991, 253: 401-406. 10.1126/science.1650499.CrossRefPubMed
51.
Cheng MT, Yang HW, Chen TH, Lee OK: Isolation and characterization of multipotent stem cells from human cruciate ligaments. Cell Prolif. 2009, 42: 448-460. 10.1111/j.1365-2184.2009.00611.x.CrossRefPubMed
52.
Rui YF, Lui PP, Li G, Fu SC, Lee YW, Chan KM: Isolation and Characterization of Multipotent Rat Tendon-Derived Stem Cells. Tissue Eng Part A. 2010, 16: 1549-1558. 10.1089/ten.tea.2009.0529.CrossRefPubMed
53.
Nagineni CN, Amiel D, Green MH, Berchuck M, Akeson WH: Characterization of the intrinsic properties of the anterior cruciate and medial collateral ligament cells: an in vitro cell culture study. J Orthop Res. 1992, 10: 465-475. 10.1002/jor.1100100402.CrossRefPubMed
54.
Indelicato PA: Non-operative treatment of complete tears of the medial collateral ligament of the knee. J Bone Joint Surg Am. 1983, 65: 323-329.PubMed
55.
Kannus P: Long-term results of conservatively treated medial collateral ligament injuries of the knee joint. Clin Orthop Relat Res. 1988, 226: 103-112.PubMed
56.
Reider B, Sathy MR, Talkington J, Blyznak N, Kollias S: Treatment of isolated medial collateral ligament injuries in athletes with early functional rehabilitation. A five-year follow-up study. Am J Sports Med. 1994, 22: 470-477. 10.1177/036354659402200406.CrossRefPubMed
57.
Frank C, Amiel D, Woo SL, Akeson W: Normal ligament properties and ligament healing. Clin Orthop Relat Res. 1985, 196: 15-25.PubMed
58.
Liang R, Woo SL, Takakura Y, Moon DK, Jia F, Abramowitch SD: Long-term effects of porcine small intestine submucosa on the healing of medial collateral ligament: a functional tissue engineering study. J Orthop Res. 2006, 24: 811-819. 10.1002/jor.20080.CrossRefPubMed
59.
Musahl V, Abramowitch SD, Gilbert TW, Tsuda E, Wang JH, Badylak SF, Woo SL: The use of porcine small intestinal submucosa to enhance the healing of the medial collateral ligament--a functional tissue engineering study in rabbits. J Orthop Res. 2004, 22: 214-220. 10.1016/S0736-0266(03)00163-3.CrossRefPubMed
Metadata
Title
Differential properties of human ACL and MCL stem cells may be responsible for their differential healing capacity
Authors
Jianying Zhang
Tiffany Pan
Hee-Jeong Im
Freddie H Fu
James HC Wang
Publication date
01-12-2011
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2011
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/1741-7015-9-68

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