Autologous, allogeneic, induced pluripotent stem cell or a combination stem cell therapy? Where are we headed in cartilage repair and why: a concise review

The evolution of articular cartilage repair procedures has resulted in a variety of cell-based therapies that use both autologous and allogeneic mesenchymal stromal cells (MSCs). As these cells are increasingly available and show promising results both in vitro and in vivo, cell-based strategies, which aim to improve ease of use and cost-effectiveness, are progressively explored. The use of MSCs in cartilage repair makes it possible to develop single-stage cell-based therapies. However, true single-stage procedures rely on one intervention, which will limit cell sources to fraction concentrates containing autologous MSCs or culture-expanded allogeneic MSCs. So far, it seems both autologous and allogeneic cells can safely be applied, but clinical studies are still ongoing and little information on clinical outcome is available. Further development of cell-based therapies may lead to clinical-grade, standardized, off-the-shelf products with easy handling for orthopedic surgeons. Although as of yet no preclinical or clinical studies are ongoing which explore the use of induced pluripotent stem cells for cartilage repair, a good manufacturing practice-grade induced pluripotent stem cell line might become the basis for such a product in the future, providing that cell fate can be controlled. The use of stem cells in clinical trials brings along new ethical issues, such as proper controls and selecting primary outcome measures. More clinical trials are needed to estimate detailed risk-benefit ratios and trials must be carefully designed to minimize risks and burdens for patients while choosing outcome measures that allow for adequate comparison with results from similar trials. In this review, we discuss the different aspects of new stem cell-based treatments, including safety and ethical issues, as well as provide an overview of current clinical trials exploring these approaches and future perspectives.

[1]  Ivan Martin,et al.  The survey on cellular and engineered tissue therapies in Europe in 2009. , 2010, Tissue engineering. Part A.

[2]  J. Skowroński,et al.  Osteochondral lesions of the knee reconstructed with mesenchymal stem cells - results. , 2013, Ortopedia, traumatologia, rehabilitacja.

[3]  M. Verhaar,et al.  Stem cell trials for cardiovascular medicine: ethical rationale. , 2014, Tissue engineering. Part A.

[4]  S. Giannini,et al.  Cartilage repair evolution in post-traumatic osteochondral lesions of the talus: from open field autologous chondrocyte to bone-marrow-derived cells transplantation. , 2010, Injury.

[5]  Y. Koh,et al.  Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. , 2012, The Knee.

[6]  Louis Casteilla,et al.  Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). , 2013, Cytotherapy.

[7]  D. Taura,et al.  Human induced pluripotent stem cells differentiated into chondrogenic lineage via generation of mesenchymal progenitor cells. , 2013, Stem cells and development.

[8]  G. Sukhikh,et al.  Human induced pluripotent stem cells derived from fetal neural stem cells successfully undergo directed differentiation into cartilage. , 2011, Stem cells and development.

[9]  J. Skowroński,et al.  Large cartilage lesions of the knee treated with bone marrow concentrate and collagen membrane--results. , 2012, Ortopedia, traumatologia, rehabilitacja.

[10]  Ivan Martin,et al.  The Survey on Cellular and Engineered Tissue Therapies in Europe in 2013. , 2016, Tissue engineering. Part A.

[11]  Farshid Guilak,et al.  Cartilage tissue engineering using differentiated and purified induced pluripotent stem cells , 2012, Proceedings of the National Academy of Sciences.

[12]  I. Martin,et al.  The survey on cellular and engineered tissue therapies in Europe in 2010. , 2012, Tissue engineering. Part A.

[13]  B. Morrey.  Osteochondral Lesions of the Knee: A New One-Step Repair Technique with Bone-Marrow-Derived Cells , 2011 .

[14]  S. Calcagno,et al.  Use of Collagen Scaffold and Autologous Bone Marrow Concentrate as a One-Step Cartilage Repair in the Knee: Histological Results of Second-Look Biopsies at 1 Year Follow-up , 2011, International journal of immunopathology and pharmacology.

[15]  S. Giannini,et al.  One-step Bone Marrow-derived Cell Transplantation in Talar Osteochondral Lesions , 2009, Clinical orthopaedics and related research.

[16]  F. Guilak,et al.  Potent induction of chondrocytic differentiation of human adipose-derived adult stem cells by bone morphogenetic protein 6. , 2006, Arthritis and rheumatism.

[17]  Y. Wei,et al.  Chondrogenic differentiation of induced pluripotent stem cells from osteoarthritic chondrocytes in alginate matrix. , 2012, European cells & materials.

[18]  Ching-Chuan Jiang,et al.  Evaluation of articular cartilage repair using biodegradable nanofibrous scaffolds in a swine model: a pilot study , 2009, Journal of tissue engineering and regenerative medicine.

[19]  D. Flanigan,et al.  Failures, re-operations, and complications after autologous chondrocyte implantation--a systematic review. , 2011, Osteoarthritis and cartilage.

[20]  W. Richter,et al.  Reduced chondrogenic potential of adipose tissue derived stromal cells correlates with an altered TGFβ receptor and BMP profile and is overcome by BMP‐6 , 2007, Journal of cellular physiology.

[21]  D. Hart,et al.  The influence of skeletal maturity on allogenic synovial mesenchymal stem cell-based repair of cartilage in a large animal model. , 2010, Biomaterials.

[22]  F. Luyten,et al.  Multipotent mesenchymal stem cells from adult human synovial membrane. , 2001, Arthritis and rheumatism.

[23]  C. Kasemkijwattana,et al.  Autologous bone marrow mesenchymal stem cells implantation for cartilage defects: two cases report. , 2011, Journal of the Medical Association of Thailand = Chotmaihet thangphaet.

[24]  Xing Zhao,et al.  Concise Review: Unraveling Stem Cell Cocultures in Regenerative Medicine: Which Cell Interactions Steer Cartilage Regeneration and How? , 2014, Stem cells translational medicine.

[25]  C. Ohlsson,et al.  Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. , 1994, The New England journal of medicine.

[26]  H. Fujioka,et al.  Treatment of a full-thickness articular cartilage defect in the femoral condyle of an athlete with autologous bone-marrow stromal cells. , 2007, Osteoarthritis and cartilage.

[27]  A. Nauta,et al.  Immunomodulatory properties of mesenchymal stromal cells. , 2007, Blood.

[28]  Thomas Aigner,et al.  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. , 2006, Arthritis and rheumatism.

[29]  Constance R. Chu,et al.  The Clinical Use of Human Culture–Expanded Autologous Bone Marrow Mesenchymal Stem Cells Transplanted on Platelet-Rich Fibrin Glue in the Treatment of Articular Cartilage Defects , 2010, Cartilage.

[30]  Mahidhar M. Durbhakula,et al.  Chondrogenic potential of progenitor cells derived from human bone marrow and adipose tissue: A patient‐matched comparison , 2005, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[31]  Hiromichi Fujie,et al.  Cartilage repair using an in vitro generated scaffold-free tissue-engineered construct derived from porcine synovial mesenchymal stem cells. , 2007, Biomaterials.

[32]  René Verdonk,et al.  Midterm Results of the Treatment of Cartilage Defects in the Knee Using Alginate Beads Containing Human Mature Allogenic Chondrocytes , 2012, The American journal of sports medicine.

[33]  Ilyas M. Khan,et al.  The surface of articular cartilage contains a progenitor cell population , 2004, Journal of Cell Science.

[34]  R. T. Allen,et al.  Analysis of Cartilage Tissue on a Cellular Level in Fresh Osteochondral Allograft Retrievals , 2007, The American journal of sports medicine.

[35]  H. Yoshikawa,et al.  Generation of hyaline cartilaginous tissue from mouse adult dermal fibroblast culture by defined factors. , 2011, The Journal of clinical investigation.

[36]  S. Giannini,et al.  One-Step Repair in Talar Osteochondral Lesions , 2013, The American journal of sports medicine.

[37]  M. Hochberg,et al.  Joint Injury in Young Adults and Risk for Subsequent Knee and Hip Osteoarthritis , 2000, Annals of Internal Medicine.

[38]  J. Kramer,et al.  Chondrogenic Differentiation in vitro of Murine Two-Factor Induced Pluripotent Stem Cells is Comparable to Murine Embryonic Stem Cells , 2012, Cells Tissues Organs.

[39]  A. Gobbi,et al.  One-Step Cartilage Repair with Bone Marrow Aspirate Concentrated Cells and Collagen Matrix in Full-Thickness Knee Cartilage Lesions , 2011, Cartilage.

[40]  L. NiemansburgSophie,et al.  Stem Cell Trials for Cardiovascular Medicine: Ethical Rationale , 2014 .

[41]  P. Emery,et al.  Synovial fluid mesenchymal stem cells in health and early osteoarthritis: detection and functional evaluation at the single-cell level. , 2008, Arthritis and rheumatism.

[42]  J. Pak.  Regeneration of human bones in hip osteonecrosis and human cartilage in knee osteoarthritis with autologous adipose-tissue-derived stem cells: a case series , 2011, Journal of medical case reports.

[43]  Y. Sakaguchi,et al.  Comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. , 2005, Arthritis and rheumatism.

[44]  M. Hochberg,et al.  Erosive Osteoarthritis , 2010 .

[45]  Shigeyuki Wakitani,et al.  Autologous Bone Marrow Stromal Cell Transplantation for Repair of Full-Thickness Articular Cartilage Defects in Human Patellae: Two Case Reports , 2004, Cell transplantation.

[46]  D. Hart,et al.  In vitro generation of a scaffold-free tissue-engineered construct (TEC) derived from human synovial mesenchymal stem cells: biological and mechanical properties and further chondrogenic potential. , 2008, Tissue engineering. Part A.

[47]  B. Sacchetti,et al.  Comparative analysis of multilineage properties of mesenchymal stromal cells derived from fetal sources shows an advantage of mesenchymal stromal cells isolated from cord blood in chondrogenic differentiation potential , 2014, Cytotherapy.

[48]  H. Yoshikawa,et al.  Direct Induction of Chondrogenic Cells from Human Dermal Fibroblast Culture by Defined Factors , 2013, PloS one.

[49]  E. Pei,et al.  Autologous Bone Marrow–Derived Mesenchymal Stem Cells Versus Autologous Chondrocyte Implantation An Observational Cohort Study , 2010 .

[50]  G. Shaw,et al.  Chondrogenic differentiation increases antidonor immune response to allogeneic mesenchymal stem cell transplantation. , 2014, Molecular therapy : the journal of the American Society of Gene Therapy.

[51]  Ilyas M. Khan,et al.  Identification and Clonal Characterisation of a Progenitor Cell Sub-Population in Normal Human Articular Cartilage , 2010, PloS one.

[52]  D. Prockop,et al.  Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. , 2006, Cytotherapy.

[53]  Hajime Ohgushi,et al.  Repair of articular cartilage defects in the patello‐femoral joint with autologous bone marrow mesenchymal cell transplantation: three case reports involving nine defects in five knees , 2007, Journal of tissue engineering and regenerative medicine.

[54]  H. Yoshikawa,et al.  Induction of chondrogenic cells from dermal fibroblast culture by defined factors does not involve a pluripotent state. , 2011, Biochemical and biophysical research communications.

[55]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[56]  H. Drissi,et al.  Efficient differentiation of human iPSC‐derived mesenchymal stem cells to chondroprogenitor cells , 2013, Journal of cellular biochemistry.

[57]  Wouter J A Dhert,et al.  Single-Stage Cell-Based Cartilage Regeneration Using a Combination of Chondrons and Mesenchymal Stromal Cells , 2013, The American journal of sports medicine.

[58]  Anders Lindahl,et al.  Footprint‐Free Human Induced Pluripotent Stem Cells From Articular Cartilage With Redifferentiation Capacity: A First Step Toward a Clinical‐Grade Cell Source , 2014, Stem cells translational medicine.

[59]  N. Adachi,et al.  Transplant of mesenchymal stem cells and hydroxyapatite ceramics to treat severe osteochondral damage after septic arthritis of the knee. , 2005, The Journal of rheumatology.

[60]  D. Saris,et al.  Functional articular cartilage repair: here, near, or is the best approach not yet clear? , 2013, Nature Reviews Rheumatology.

[61]  A. Abbas,et al.  Human peripheral blood derived mesenchymal stem cells demonstrate similar characteristics and chondrogenic differentiation potential to bone marrow derived mesenchymal stem cells , 2012, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[62]  Ping Chen,et al.  Comparative analysis of mesenchymal stem cells from bone marrow, cartilage, and adipose tissue. , 2008, Stem cells and development.