Abstract
Osteoarthritis (OA) is the most common chronic disabling condition effecting the elderly, significantly impacting an individual patient’s quality of life. Current treatment options for OA are focused on pain management and slowing degradation of cartilage. Some modern surgical techniques aimed at encouraging regeneration at defect sites have met with limited long-term success. Mesenchymal stem cells (MSCs) have been viewed recently as a potential tool in OA repair due to their chondrogenic capacity. Several studies have shown success with regards to reducing patient’s OA-related pain and discomfort but have been less successful in inducing chondrocyte regeneration. The heterogeneity of MSCs and their limited proliferation capacity also raises issues when developing an off-the-shelf treatment for OA. Induced pluripotent stem cell (iPSC) technology, which allows for the easy production of cells capable of prolonged self-renewal and producing any somatic cell type, may overcome those limitations. Patient derived iPSCs can also be used to gain new insight into heredity-related OA. Efforts to generate chondrocytes from iPSCs through embryoid bodies or mesenchymal intermediate stages have struggled to produce with optimal functional characteristics. However, iPSCs potential to produce cells for future OA therapies has been supported by iPSC-derived teratomas, which have shown an ability to produce functional, stable articular cartilage. Other iPSCs-chondrogenic protocols are also improving by incorporating tissue engineering techniques to better mimic developmental conditions.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- AC:
-
articular cartilage
- ACT:
-
autologous cartilage transplantation
- BMP:
-
Bone Morphogenetic Protein
- ECM:
-
extracellular matrix
- ESC:
-
Embryonic Stem Cell
- FOCD:
-
Familial osteochondritis dissecans
- HALPN1:
-
Hyaluronan and proteoglycan link protein 1
- ICM:
-
Inner Cell Mass
- IGF-1:
-
Insulin-Like Growth Factor 1
- iMPC:
-
intermediate Mesenchymal Progenitor Cell
- iPSC:
-
induced Pluripotent Stem Cell
- KLF4:
-
gut-enriched Krüppel-like factor
- MSC:
-
Mesenchymal Stem Cell
- OA:
-
Osteoarthritis
- Oct-4:
-
octamer-binding transcription factor 4
- SOX:
-
Sry-related HMG box
- SRY:
-
Sex-Determining Region Y-Box
- TGF-β:
-
Transforming Growth Factor-beta
- WHO:
-
Word Health Organisation
- WNT4:
-
WNT Family Member 4
References
Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105(4):1815–1822. https://doi.org/10.1182/blood-2004-04-1559
Amthor H, Christ B, Weil M, Patel K (1998) The importance of timing differentiation during limb muscle development. Curr Biol 8(11):642–652. https://doi.org/10.1016/s0960-9822(98)70251-9
Browne JE, Branch TP (2000) Surgical alternatives for treatment of articular cartilage lesions. J Am Acad Orthop Surg 8(3):180–189. https://doi.org/10.5435/00124635-200005000-00005
Browne JE, Anderson AF, Arciero R, Mandelbaum B, Moseley JB, Micheli LJ, Lyle J, Fu F, Erggelet C (2005) Clinical outcome of autologous chondrocyte implantation at 5 years in US subjects. Clin Orthop Relat Res 436:237–245
Caldwell K, Wang J (2015) Cell-based articular cartilage repair: the link between development and regeneration. Osteoarthr Cartil 23(3):351–362. https://doi.org/10.1016/j.joca.2014.11.004
Cao L, McDonnell A, Nitzsche A, Alexandrou A, Saintot PP, Loucif AJC, Brown AR, Young G, Mis M, Randall A, Waxman SG, Stanley P, Kirby S, Tarabar S, Gutteridge A, Butt R, McKernan RM, Whiting P, Ali Z, Bilsland J, Stevens EB (2016) Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia. Sci Transl Med 8(335). https://doi.org/10.1126/scitranslmed.aad76533
Caplan N, Kader DF (2013) Two- to 9-year outcome after autologous chondrocyte transplantation of the knee. In: Classic papers in orthopaedics. Springer, London, pp 165–168. https://doi.org/10.1007/978-1-4471-5451-8_40
Centeno CJ, Schultz JR, Cheever M, Freeman M, Faulkner S, Robinson B, Hanson R (2011) Safety and complications reporting update on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther 6(4):368–378. https://doi.org/10.2174/157488811797904371
Clinical Study of Umbilical Cord Tissue Mesenchymal Stem Cells (UC-MSC) for Treatment of Osteoarthritis – Full Text View – ClinicalTrials.gov. (n.d.) https://clinicaltrials.gov/ct2/show/NCT02237846?term=Mesenchymal+Stem+Cell+osteoarthritis&recr=Active%2C+not+recruiting&rank=1. Accessed 10 May 2017
Diederichs S, Tuan RS (2014) Functional comparison of human-induced pluripotent stem cell-derived mesenchymal cells and bone marrow-derived mesenchymal stromal cells from the same donor. Stem Cells Dev 23(14):1594–1610. https://doi.org/10.1089/scd.2013.0477
Diederichs S, Gabler J, Autenrieth J, Kynast KL, Merle C, Walles H, Utikal J, Richter W (2016) Differential regulation of SOX9 protein during Chondrogenesis of induced pluripotent stem cells versus mesenchymal stromal cells: a shortcoming for cartilage formation. Stem Cells Dev 25(8):598–609. https://doi.org/10.1089/scd.2015.0312
Diekman BO, Christoforou N, Willard VP, Sun H, Sanchez-Adams J, Leong KW, Guilak F (2012) Cartilage tissue engineering using differentiated and purified induced pluripotent stem cells. Proc Natl Acad Sci 109(47):19172–19177. https://doi.org/10.1073/pnas.1210422109
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop DJ, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8(4):315–317. https://doi.org/10.1080/14653240600855905
Esseltine JL, Shao Q, Brooks C, Sampson J, Betts DH, Séguin CA, Laird DW (2017) Connexin43 mutant patient-derived induced pluripotent stem cells exhibit altered differentiation potential. J Bone Miner Res. https://doi.org/10.1002/jbmr.3098
Freitag J, Bates D, Boyd R, Shah K, Barnard A, Huguenin L, Tenen A (2016) Mesenchymal stem cell therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy – a review. BMC Musculoskelet Disord 17(1). https://doi.org/10.1186/s12891-016-1085-9
Fukui N, Purple CR, Sandell LJ (2001) Cell biology of osteoarthritis: the chondrocyte’s response to injury. Curr Rheumatol Rep 3(6):496–505. https://doi.org/10.1007/s11926-001-0064-8
Grigolo B, Lisignoli G, Desando G, Cavallo C, Marconi E, Tschon M, Tschon M, Giavaresi G, Fini M, Giardino R, Facchini A (2009) Osteoarthritis treated with mesenchymal stem cells on hyaluronan-based scaffold in rabbit. Tissue Eng Part C Methods 15(4):647–658. https://doi.org/10.1089/ten.TEC.2008.0569
Gupta A, Niger C, Buo AM, Eidelman ER, Chen RJ, Stains JP (2014) Connexin43 enhances the expression of osteoarthritis-associated genes in synovial fibroblasts in culture. BMC Musculoskelet Disord 15(1). https://doi.org/10.1186/1471-2474-15-425
Gupta PK, Chullikana A, Rengasamy M, Shetty N, Pandey V, Agarwal V, Majumdar AS (2016) Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®): preclinical and clinical trial in osteoarthritis of the knee joint. Arthritis Res Ther 18(1). https://doi.org/10.1186/s13075-016-1195-7
Halvaei M, Abolfathi N, Shokrgozar M, Eskandari M, Haghighipour N, Navaee F (2016) A new mechanical micro-bioreactor for cartilage tissue. Tissue Eng 22(Suppl 1):94–95. doi:EPFL-CONF-224956
Herberts P, Malchau H (2000) Long-term registration has improved the quality of hip replacement: a review of the Swedish THR register comparing 160,000 cases. Acta Orthop Scand 71(2):111–121. https://doi.org/10.1080/0001
Hill TP, Später D, Taketo MM, Birchmeier W, Hartmann C (2005) Canonical Wnt/β-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell 8(5):727–738. https://doi.org/10.1016/j.devcel.2005.02.013
Ito MM, Kida MY (2000) Morphological and biochemical re-evaluation of the process of cavitation in the rat knee joint: cellular and cell strata alterations in the interzone. J Anat 197(4):659–679. https://doi.org/10.1046/j.1469-7580.2000.19740659
Iwamoto M, Tamamura Y, Koyama E, Komori T, Takeshita N, Williams JA, Pacifici M (2007) Transcription factor ERG and joint and articular cartilage formation during mouse limb and spine skeletogenesis. Dev Biol 305(1):40–51. https://doi.org/10.1016/j.ydbio.2007.01.037
Joswig A, Mitchell A, Cummings KJ, Levine GJ, Gregory CA, Smith R, Watts AE (2017) Repeated intra-articular injection of allogeneic mesenchymal stem cells causes an adverse response compared to autologous cells in the equine model. Stem Cell Res Ther 8(1). https://doi.org/10.1186/s13287-017-0503-8
Kern S, Eichler H, Stoeve J, Klüter H, Bieback K (2006) Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 24(5):1294–1301. https://doi.org/10.1634/stemcells.2005-0342
Koch P, Opitz T, Steinbeck JA, Ladewig J, Brustle O (2009) A rosette-type, self-renewing human ES cell-derived neural stem cell with potential for in vitro instruction and synaptic integration. Proc Natl Acad Sci 106(9):3225–3230. https://doi.org/10.1073/pnas.0808387106
Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA (2007) Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: part II. Arthritis Rheum 58(1):26–35. https://doi.org/10.1002/art.23176
Layh-Schmitt G, Lu S, Navid F, Brooks SR, Lazowick E, Davis K, Montag C, Gadina M, Colbert RA (2016) Generation and differentiation of induced pluripotent stem cells reveal ankylosing spondylitis risk gene expression in bone progenitors. Clin Rheumatol 36(1):143–154. https://doi.org/10.1007/s10067-016-3469-5
Lietman SA (2016) Induced pluripotent stem cells in cartilage repair. World J Orthop 7(3):149. https://doi.org/10.5312/wjo.v7.i3.149
Loeser RF (2011) Aging and osteoarthritis. Curr Opin Rheumatol 23(5):492–496. https://doi.org/10.1097/BOR.0b013e3283494005
Longobardi L, O’Rear L, Aakula S, Johnstone B, Shimer K, Chytil A, Horton WA, Moses HL, Spagnoli A (2005) Effect of IGF-I in the chondrogenesis of bone marrow mesenchymal stem cells in the presence or absence of TGF-β signaling. J Bone Miner Res 21(4):626–636. https://doi.org/10.1359/jbmr.051213
Makris EA, Gomoll AH, Malizos KN, JC H, Athanasiou KA (2015) Repair and tissue engineering techniques for articular cartilage. Nat Rev Rheumatol 11(1):21–34. https://doi.org/10.1038/nrrheum.2014.157
Muchmore L, Lynch WD, Gardner HH, Williamson T, Burke T (2003) Prevalence of arthritis and associated joint disorders in an employed population and the associated healthcare, sick leave, disability, and workers’ compensation benefits cost and productivity loss for employers. J Occup Environ Med 45(4):369–378. https://doi.org/10.1097/01.jom.0000063621.37065.26
Murphy L, Helmick CG (2012) The impact of osteoarthritis in the United States. Orthop Nurs 31(2):85–91. https://doi.org/10.1097/nor.0b013e31824fcd42
Nakagawa T, Lee SY, Reddi AH (2009) Induction of chondrogenesis from human embryonic stem cells without embryoid body formation by bone morphogenetic protein 7 and transforming growth factor β1. Arthritis Rheum 60(12):3686–3692. https://doi.org/10.1002/art.27229
Nejadnik H, Hui JH, Choong EP, Tai B, Lee EH (2010) Autologous bone marrow–derived mesenchymal stem cells versus autologous chondrocyte implantation. Am J Sports Med 38(6):1110–1116. https://doi.org/10.1177/0363546509359067
Nejadnik H, Diecke S, Lenkov OD, Chapelin F, Donig J, Tong X, Derugin N, Chan RC, Gaur A, Yang F, JC W, Daldrup-Link HE (2015) Improved approach for chondrogenic differentiation of human induced pluripotent stem cells. Stem Cell Rev Rep 11(2):242–253. https://doi.org/10.1007/s12015-014-9581-5
Neogi T (2013) The epidemiology and impact of pain in osteoarthritis. Osteoarthr Cartil 21(9):1145–1153. https://doi.org/10.1016/j.joca.2013.03.018
Nguyen D, Hägg DA, Forsman A, Ekholm J, Nimkingratana P, Brantsing C, Kalogeropoulos T, Zaunz S, Concaro S, Brittberg M, Lindahl A, Gatenholm P, Enejder A, Simonsson S (2017) Cartilage tissue engineering by the 3D bioprinting of iPS cells in a nanocellulose/alginate bioink. Sci Rep 7(1). https://doi.org/10.1038/s41598-017-00690-y
Nowlan NC, Bourdon C, Dumas G, Tajbakhsh S, Prendergast PJ, Murphy P (2010) Developing bones are differentially affected by compromised skeletal muscle formation. Bone 46(5):1275–1285. https://doi.org/10.1016/j.bone.2009.11.026
Pearle AD, Warren RF, Rodeo SA (2005) Basic science of articular cartilage and osteoarthritis. Clin Sports Med 24(1):1–12. https://doi.org/10.1016/j.csm.2004.08.007
Pelttari K, Winter A, Steck E, Goetzke K, Hennig T, Ochs BG, Ainger T, Richter W (2006) Premature induction of hypertrophy during in vitro chondrogenesis of human mesenchymal stem cells correlates with calcification and vascular invasion after ectopic transplantation in SCID mice. Arthritis Rheum 54(10):3254–3266. https://doi.org/10.1002/art.22136
Peterson L, Vasiliadis HS, Brittberg M, Lindahl A (2010) Autologous chondrocyte implantation a long-term follow-up. Am J Sports Med 38(6):1117–1124. https://doi.org/10.1177/0363546509357915
Pfander D, Swoboda B, Kirsch T (2001) Expression of early and late differentiation markers (proliferating cell nuclear antigen, syndecan-3, annexin VI, and alkaline phosphatase) by human osteoarthritic chondrocytes. Am J Pathol 159(5):1777–1783. https://doi.org/10.1016/s0002-9440(10)63024-6
Qu C, Puttonen KA, Lindeberg H, Ruponen M, Hovatta O, Koistinaho J, Lammi MJ (2013) Chondrogenic differentiation of human pluripotent stem cells in chondrocyte co-culture. Int J Biochem Cell Biol 45(8):1802–1812. https://doi.org/10.1016/j.biocel.2013.05.029
Rodríguez JI, Palacios J, García-Alix A, Pastor I, Paniagua R (1988) Effects of immobilization on fetal bone development. A morphometric study in newborns with congenital neuromuscular diseases with intrauterine onset. Calcif Tissue Int 43(6):335–339. https://doi.org/10.1007/bf02553275
Russell KC, Phinney DG, Lacey MR, Barrilleaux BL, Meyertholen KE, Oconnor KC (2010) In vitro high-capacity assay to quantify the clonal heterogeneity in trilineage potential of mesenchymal stem cells reveals a complex hierarchy of lineage commitment. Stem Cells 28(4):788–798. https://doi.org/10.1002/stem.312
Saase JL, Romunde LK, Cats A, Vandenbroucke JP, Valkenburg HA (1989) Epidemiology of osteoarthritis: Zoetermeer survey. Comparison of radiological osteoarthritis in a Dutch population with that in 10 other populations. Ann Rheum Dis 48(4):271–280. https://doi.org/10.1136/ard.48.4.271
Shi Y, Inoue H, Wu JC, Yamanaka S (2016) Induced pluripotent stem cell technology: a decade of progress. Nat Rev Drug Discov 16(2):115–130. https://doi.org/10.1038/nrd.2016.245
Shiba Y, Fernandes S, Zhu WZ, Filice D, Muskheli V, Kim J, Palpant NJ, Gantz J, Moyes KW, Reinecke H, Van Biber B, Dardas T, Mignone JL, Izawa A, Hanna R, Viswanathan M, Gold JD, Kotlikoff MI, Sarvazyan N, Kay MW, Murry CE, Laflamme MA (2012) Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts. Nature 489(7415):322–325. https://doi.org/10.1038/nature11317
Soler R, Orozco L, Munar A, Huguet M, López R, Vives J, Garcia-Lopez J (2016) Final results of a phase I–II trial using ex vivo expanded autologous mesenchymal stromal cells for the treatment of osteoarthritis of the knee confirming safety and suggesting cartilage regeneration. Knee 23(4):647–654. https://doi.org/10.1016/j.knee.2015.08.013
Spagnoli A, O’Rear L, Chandler RL, Granero-Molto F, Mortlock DP, Gorska AE, Weis JA, Longobardi L, Chytil A, Shimer K, Moses HL (2007) TGF-β signaling is essential for joint morphogenesis. J Cell Biol 177(6):1105–1117. https://doi.org/10.1083/jcb.200611031
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872. https://doi.org/10.1016/j.cell.2007.11.019
Trounson A, DeWitt ND (2016) Pluripotent stem cells progressing to the clinic. Nat Rev Mol Cell Biol 17(3):194–200. https://doi.org/10.1038/nrm.2016.10
Use of Adipose Tissue Derived Mesenchymal Stem Cells for Knee Osteoarthrosis – Full Text View-ClinicalTrials.gov. (n.d.) https://clinicaltrials.gov/ct2/show/NCT02966951term=Mesenchymal+Stem+Cell+osteoarthritis recr=Open rank=2. Accessed 10 May 2017
Wang Y, Wu M, Cheung MP, Sham MH, Akiyama H, Chan D, Cheah KS, Cheung M (2017) Reprogramming of dermal fibroblasts into osteo-chondrogenic cells with elevated osteogenic potency by defined transcription factors. Stem Cell Rep 8(6):1587–1599. https://doi.org/10.1016/j.stemcr.2017.04.018
Wehrli BM, Huang W, De Crombrugghe B, Ayala AG, Czerniak B (2003) Sox9, a master regulator of chondrogenesis, distinguishes mesenchymal chondrosarcoma from other small blue round cell tumors. Hum Pathol, 34(3):263–269. http://dx.doi.org/10.1053/hupa.2003.41
Xu M, Stattin E, Shaw G, Heinegård D, Sullivan G, Wilmut I, Colman A, Önnerfjord P, Khabut A, Aspberg A, Dockery P, Hardingham T, Murphy M, Barry F (2016) Chondrocytes derived from mesenchymal stromal cells and induced pluripotent cells of patients with familial osteochondritis dissecans exhibit an endoplasmic reticulum stress response and defective matrix assembly. Stem Cells Transl Med 5(9):1171–1181. https://doi.org/10.5966/sctm.2015-0384
Yamashita A, Morioka M, Yahara Y, Okada M, Kobayashi T, Kuriyama S, Matsuda S, Tsumaki N (2015) Generation of scaffoldless hyaline cartilaginous tissue from human iPSCs. Stem Cell Rep 4(3):404–418. https://doi.org/10.1016/j.stemcr.2015.01.016
Zhu Y, Wang Y, Zhao B, Niu X, Hu B, Li Q, Zhang J, Ding J, Chen Y, Wang Y (2017) Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis. Stem Cell Res Ther 8(1). https://doi.org/10.1186/s13287-017-0510-9
Acknowledgements
The authors would like to acknowledge Miss Roxana Mobasheri for the artwork in Fig. 1 and current and previous members of their laboratories and their internal and external collaborators for their contributions.
Funding
This work was supported by grants from EU FP7 projects (D-BOARD, HEALTH-F2-2012-305815; EpiHealthNet, PITN-GA-2012-317146). A.M. is coordinator of the D-BOARD Consortium funded by European Commission Framework 7 programme (EU FP7; HEALTH.2012.2.4.5-2, project number 305815, Novel Diagnostics and Biomarkers for Early Identification of Chronic Inflammatory Joint Diseases, awarded to AM), and member of the Arthritis Research UK Centre for Sport, Exercise, and Osteoarthritis, funded by Arthritis Research UK (Grant Reference: 20194). A.M. are members of the Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) consortium, a 5-year project funded by the European Commission’s Innovative Medicines Initiative (IMI). APPROACH is a public-private partnership directed towards osteoarthritis biomarker development through the establishment of a heavily phenotyped and comprehensively analyzed longitudinal cohort. A.M. has received partial support from the Innovative Medicines Initiative (IMI) Joint Undertaking under grant agreement no. 115770, resources of which are composed of financial contribution from the European Union’s Seventh Framework programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. A.M. has also received funding from the European Union through a Marie Skłodowska-Curie scheme (project number 625746; acronym: CHONDRION; FP7-PEOPLE-2013-IEF). This work has also received financial support from the European Social Fund according to the activity ‘Improvement of researchers’ qualification by implementing world-class R&D projects’ of Measure No. 09.3.3-LMT-K-712.
Ethics Approval and Consent to Participate
Not applicable.
Consent for Publication
Not applicable.
Availability of Data and Material
Not applicable.
Competing Interests
AM declares that he has served as a scientific Advisory Board Member for AbbVie and has received honoraria from AbbVie and Bioiberica. The other authors declare that they have no competing interests.
Authors’ contributions
CM, ZT and JK proposed the concept and wrote the manuscript, AD read and approved the paper. AM read and edited the manuscript before submission. All authors read and approved the final version of the paper.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing AG
About this chapter
Cite this chapter
Murphy, C., Mobasheri, A., Táncos, Z., Kobolák, J., Dinnyés, A. (2017). The Potency of Induced Pluripotent Stem Cells in Cartilage Regeneration and Osteoarthritis Treatment. In: Turksen, K. (eds) Cell Biology and Translational Medicine, Volume 1. Advances in Experimental Medicine and Biology(), vol 1079. Springer, Cham. https://doi.org/10.1007/5584_2017_141
Download citation
DOI: https://doi.org/10.1007/5584_2017_141
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-93866-0
Online ISBN: 978-3-319-93867-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)