title: Differentiation potential of limbal fibroblasts and bone marrow mesenchymal stem cells to corneal epithelial cells.
abstract: The cornea is covered by a stratified epithelium that is renewed by stem cells located in the peripheral region of the cornea known as the limbus. This stroma of the limbus contains stromal keratocytes that, when expanded in culture, are termed limbal fibroblasts (LFs). It is thought that LFs exhibit similar characteristics to bone marrow mesenchymal stem cells (BM MSCs) and help maintain the epithelial stem cell phenotype in the limbal region. In this study, we aimed at reprogramming stage-specific embryonic antigen-4 (SSEA4+) LFs and BM MSCs into corneal epithelial lineage using a three-dimensional culture system and embryonic stem cell medium. After enrichment, SSEA4+ cells showed a higher level of stem cell marker expression such as Sox2, Oct4, Nanog, Rex1, ABCG2, and TRA-1-60, and colony-forming efficiency than did SSEA4- cells. SSEA4+, as compared to SSEA4- cells, had a greater propensity to form spheres that, in turn, were induced into ectodermal lineage and further differentiated into functional corneal epithelium. Results show that LFs were similar to BM MSCs in marker profiles, and together with the differences noted between SSEA4+ and SSEA4- cells, point to LFs' being tissue-specific MSCs. However, LFs showed a greater potential for differentiation into corneal epithelium, indicating the potential importance of tissue-specific adult progenitors in their reprogramming capacity into cells of interest. This study opens a new avenue for investigating the molecular mechanism involved in maintaining a limbal stem cell niche and thus a potentially important clinical application to treat corneal epithelial stem cell loss.
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, Massachusetts, USA.
authors.forename: Kishore Reddy
authors.initials: KR
authors.lastname: Katikireddy
authors.forename: Reza
authors.initials: R
authors.lastname: Dana
authors.forename: Ula V
authors.initials: UV
authors.lastname: Jurkunas
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002469:Cell Separation; D002478:Cells, Cultured; D004475:Ectoderm / Q000166:cytology; D017097:Electric Impedance; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D019573:Epithelium, Corneal / Q000166:cytology*; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D016850:Limbus Corneae / Q000166:cytology*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D008954:Models, Biological; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D055746:Stage-Specific Embryonic Antigens / Q000378:metabolism
chemical_list: D015415:Biomarkers; D055746:Stage-Specific Embryonic Antigens; C066584:stage-specific embryonic antigen-4
keywords: Bone marrow mesenchymal stem cells; Corneal epithelial stem cells; Limbal fibroblasts; Limbal niche; Stage-specific embryonic antigen-4
references.citation: Stem Cells. 2008 Feb;26(2):440-4
references.pmid: 18032703
references.citation: Stem Cells. 2007 May;25(5):1145-55
references.pmid: 17255521
references.citation: Blood. 2007 Feb 15;109(4):1743-51
references.pmid: 17062733
references.citation: Stem Cells. 2004;22(3):355-66
references.pmid: 15153612
references.citation: Annu Rev Cell Dev Biol. 2003;19:207-35
references.pmid: 14570569
references.citation: Exp Eye Res. 2010 Sep;91(3):326-35
references.pmid: 20599432
references.citation: Stem Cells. 2002;20(4):329-37
references.pmid: 12110702
references.citation: Biol Cell. 2005 Apr;97(4):265-76
references.pmid: 15762848
references.citation: Stem Cells. 2005 Oct;23(9):1266-75
references.pmid: 16051989
references.citation: Exp Eye Res. 2009 Sep;89(3):426-31
references.pmid: 19409893
references.citation: Exp Eye Res. 2011 Jan;92(1):10-9
references.pmid: 20970420
references.citation: Invest Ophthalmol Vis Sci. 2009 Dec;50(12):5672-80
references.pmid: 19661227
references.citation: J Cell Biochem. 2008 Dec 15;105(6):1352-60
references.pmid: 18980213
references.citation: Curr Stem Cell Res Ther. 2006 Sep;1(3):365-9
references.pmid: 18220880
references.citation: Stem Cells. 2009 Dec;27(12):3053-62
references.pmid: 19859985
references.citation: Invest Ophthalmol Vis Sci. 2003 Jun;44(6):2496-506
references.pmid: 12766048
references.citation: Stem Cells. 2012 Jun;30(6):1059-63
references.pmid: 22489057
references.citation: J Invest Dermatol. 2011 Apr;131(4):857-64
references.pmid: 21150926
references.citation: Invest Ophthalmol Vis Sci. 2001 Nov;42(12):2942-8
references.pmid: 11687540
references.citation: Mol Vis. 2008 Mar 04;14:431-42
references.pmid: 18334960
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15625-30
references.pmid: 14663151
references.citation: Mol Vis. 2009;15:99-107
references.pmid: 19156227
references.citation: Brain Res Dev Brain Res. 2005 Dec 7;160(2):239-51
references.pmid: 16253345
references.citation: J Cell Biol. 1986 Jul;103(1):49-62
references.pmid: 2424919
references.citation: Sci Rep. 2013;3:1179
references.pmid: 23378912
references.citation: Invest Ophthalmol Vis Sci. 2012 Jan 25;53(1):279-86
references.pmid: 22167096
references.citation: Br J Ophthalmol. 2005 May;89(5):529-32
references.pmid: 15834076
references.citation: APMIS. 2013 Jul;121(7):612-25
references.pmid: 23216104
references.citation: Tissue Eng. 2006 Apr;12(4):665-79
references.pmid: 16674282
references.citation: Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3156-61
references.pmid: 11248048
references.citation: Stem Cell Rev Rep. 2012 Sep;8(3):696-705
references.pmid: 21964568
references.citation: Invest Ophthalmol Vis Sci. 2003 Oct;44(10):4275-81
references.pmid: 14507871
references.citation: Zhonghua Yan Ke Za Zhi. 2010 Aug;46(8):719-24
references.pmid: 21054997
references.citation: Mol Vis. 2012;18:1289-300
references.pmid: 22665977
references.citation: PLoS One. 2011;6(12):e28856
references.pmid: 22174914
references.citation: Invest Ophthalmol Vis Sci. 2006 Nov;47(11):4780-6
references.pmid: 17065488
references.citation: Stem Cells. 2008 Feb;26(2):372-80
references.pmid: 17962700
references.citation: Invest Ophthalmol Vis Sci. 2007 Jan;48(1):144-56
references.pmid: 17197527
references.citation: Stem Cells. 2006 Feb;24(2):315-21
references.pmid: 16109757
references.citation: PLoS One. 2012;7(9):e45435
references.pmid: 23029008
references.citation: Biomaterials. 2013 Apr;34(13):3215-22
references.pmid: 23439133