Stem cell research and clinical development in tendon repair.

Stem cells are one of the most fascinating areas in regenerative medicine today. They play a crucial role in development and regeneration and are defined as cells that continuously reproduce themselves while maintaining the ability to differentiate into various cell types. Stem cells are found at all developmental stages, from embryonic stem cells (ESCs) which differentiate into all cell types, to adult stem cells (ASCs) which are responsible for tissue regeneration. Studies using animal models have shown promising results following cell therapy for induced injury in musculoskeletal system, including tendon healing, but the results can be variable. Alternative sources for cell therapy in tendon pathology may include ESCs, ASCs (bone marrow, adipose tissue or tendon derived stem cells) or induced pluripotent stem cells (iPSCs). While ethical and safety concerns currently forbid clinical application of ESCs and iPSCs, initial clinical trials with ASCs are promising.

[1]  Yu Suk Choi,et al.  Age-related alterations in mesenchymal stem cells related to shift in differentiation from osteogenic to adipogenic potential: Implication to age-associated bone diseases and defects , 2012, Mechanisms of Ageing and Development.

[2]  B. Maier,et al.  Inducible pluripotent stem cells: not quite ready for prime time? , 2010, Current opinion in organ transplantation.

[3]  Boon Chin Heng,et al.  Efficacy of hESC-MSCs in knitted silk-collagen scaffold for tendon tissue engineering and their roles. , 2010, Biomaterials.

[4]  C. Eaves,et al.  Hematopoietic stem cell heterogeneity takes center stage. , 2012, Cell stem cell.

[5]  J. Itskovitz‐Eldor,et al.  Repair of full-thickness tendon injury using connective tissue progenitors efficiently derived from human embryonic stem cells and fetal tissues. , 2010, Tissue engineering. Part A.

[6]  L. E. Young,et al.  Somatic cell nuclear transfer , 2002, Nature.

[7]  A. Watts,et al.  Cell- and gene-based approaches to tendon regeneration. , 2012, Journal of shoulder and elbow surgery.

[8]  A. Bayés‐Genís,et al.  Umbilical cord blood for cardiovascular cell therapy: from promise to fact , 2012, Annals of the New York Academy of Sciences.

[9]  R. L. Smith,et al.  Viability and proliferation of pluripotential cells delivered to tendon repair sites using bioactive sutures--an in vitro study. , 2011, The Journal of hand surgery.

[10]  R. Lovell-Badge,et al.  The Vascular Stem Cell Niche , 2012, Journal of Cardiovascular Translational Research.

[11]  Yufang Shi,et al.  How mesenchymal stem cells interact with tissue immune responses. , 2012, Trends in immunology.

[12]  R Cancedda,et al.  Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model. , 2000, Journal of cell science.

[13]  A. Friedenstein,et al.  STROMAL CELLS RESPONSIBLE FOR TRANSFERRING THE MICROENVIRONMENT OF THE HEMOPOIETIC TISSUES: Cloning In Vitro and Retransplantation In Vivo , 1974, Transplantation.

[14]  P. Zandstra,et al.  LIF‐mediated control of embryonic stem cell self‐renewal emerges due to an autoregulatory loop , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  Giacomo Rossi,et al.  Histological and Immunohistochemical Evaluation of Autologous Cultured Bone Marrow Mesenchymal Stem Cells and Bone Marrow Mononucleated Cells in Collagenase-Induced Tendinitis of Equine Superficial Digital Flexor Tendon , 2010, Veterinary medicine international.

[16]  D. Smith.  Cell Therapy in Tendon Disorders: What Is the Current Evidence? , 2012 .

[17]  A. Nagy,et al.  Induced Pluripotent Stem Cell Lines Derived from Equine Fibroblasts , 2011, Stem Cell Reviews and Reports.

[18]  P. Beredjiklian,et al.  Regenerative properties of fetal sheep tendon are not adversely affected by transplantation into an adult environment , 2006, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[19]  M. Kaufman,et al.  Establishment in culture of pluripotential cells from mouse embryos , 1981, Nature.

[20]  S. Schwartz,et al.  Embryonic stem cell trials for macular degeneration: a preliminary report , 2012, The Lancet.

[21]  Zi Yin,et al.  Stepwise Differentiation of Human Embryonic Stem Cells Promotes Tendon Regeneration by Secreting Fetal Tendon Matrix and Differentiation Factors , 2009, Stem cells.

[22]  A. Uccelli,et al.  Mesenchymal stem cells in health and disease , 2008, Nature Reviews Immunology.

[23]  A. Cowin,et al.  Expression of TGF-beta and its receptors in murine fetal and adult dermal wounds. , 2001, European journal of dermatology : EJD.

[24]  D. Roop,et al.  Osteoblasts Derived from Induced Pluripotent Stem Cells form Calcified Structures in Scaffolds Both In Vitro and In Vivo , 2011, Stem cells.

[25]  Hicham Drissi,et al.  Rapid Isolation of Human Stem Cells (Connective Tissue Progenitor Cells) From the Proximal Humerus During Arthroscopic Rotator Cuff Surgery , 2010, The American journal of sports medicine.

[26]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[27]  Armand Keating,et al.  Mesenchymal stromal cells: new directions. , 2012, Cell Stem Cell.

[28]  T. Stout,et al.  Equine embryos and embryonic stem cells: defining reliable markers of pluripotency. , 2010, Theriogenology.

[29]  Yichi Zhang,et al.  Peripheral Blood Stem Cells: Phenotypic Diversity and Potential Clinical Applications , 2012, Stem Cell Reviews and Reports.

[30]  N. Kulagina,et al.  Fibroblast precursors in normal and irradiated mouse hematopoietic organs. , 1976, Experimental hematology.

[31]  R. Pochampally,et al.  Isolation of a Highly Clonogenic and Multipotential Subfraction of Adult Stem Cells from Bone Marrow Stroma , 2004, Stem cells.

[32]  H. Schöler,et al.  Formation of Pluripotent Stem Cells in the Mammalian Embryo Depends on the POU Transcription Factor Oct4 , 1998, Cell.

[33]  H. Ouyang,et al.  Stem cells for tendon tissue engineering and regeneration , 2010, Expert opinion on biological therapy.

[34]  João L. Ellera Gomes,et al.  Conventional rotator cuff repair complemented by the aid of mononuclear autologous stem cells , 2011, Knee Surgery, Sports Traumatology, Arthroscopy.

[35]  Shi-Lung Lin.  Concise Review: Deciphering the Mechanism Behind Induced Pluripotent Stem Cell Generation , 2011, Stem cells.

[36]  Marian F Young,et al.  Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche , 2007, Nature Medicine.

[37]  J. Till,et al.  A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. , 1961, Radiation research.

[38]  S. Badylak,et al.  A perivascular origin for mesenchymal stem cells in multiple human organs. , 2008, Cell stem cell.

[39]  Sean P. Palecek,et al.  Functional Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells , 2009, Circulation research.

[40]  Parinya Noisa,et al.  Technical Challenges in the Derivation of Human Pluripotent Cells , 2011, Stem cells international.

[41]  R. Brooks,et al.  Exploring the application of stem cells in tendon repair and regeneration. , 2012, Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association.

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

[43]  D. Kaufman,et al.  Multilineage Differentiation from Human Embryonic Stem Cell Lines , 2001, Stem cells.

[44]  A. Goodship,et al.  The pathobiology and repair of tendon and ligament injury. , 1994, The Veterinary clinics of North America. Equine practice.

[45]  P. Beredjiklian,et al.  Regenerative Versus Reparative Healing in Tendon: A Study of Biomechanical and Histological Properties in Fetal Sheep , 2003, Annals of Biomedical Engineering.

[46]  Ji Young Kim,et al.  Robust Enhancement of Neural Differentiation from Human ES and iPS Cells Regardless of their Innate Difference in Differentiation Propensity , 2010, Stem Cell Reviews and Reports.

[47]  L. Lajtha,et al.  A comparison of cell replacement in bone marrow, testis and three regions of surface epithelium. , 1979, Biochimica et biophysica acta.

[48]  B. Thiers.  Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors , 2008 .

[49]  Masaki Ieda,et al.  Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. , 2010, Cell.

[50]  A. Watts,et al.  Fetal derived embryonic-like stem cells improve healing in a large animal flexor tendonitis model , 2011, Stem Cell Research & Therapy.

[51]  Robert Lanza,et al.  Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. , 2009, Cell stem cell.

[52]  J. Thomson,et al.  Embryonic stem cell lines derived from human blastocysts. , 1998, Science.

[53]  Yin Mei Wong,et al.  Tendon‐derived stem cells (TDSCs) promote tendon repair in a rat patellar tendon window defect model , 2012, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[54]  A. D. Panopoulos,et al.  Induced pluripotent stem cells in clinical hematology: potentials, progress, and remaining obstacles , 2012, Current opinion in hematology.

[55]  M. Russo,et al.  A new clinical approach: use of blood-derived stem cells (BDSCs) for superficial digital flexor tendon injuries in horses. , 2012, Life sciences.

[56]  J. Till,et al.  THE DISTRIBUTION OF COLONY-FORMING CELLS AMONG SPLEEN COLONIES. , 1963, Journal of cellular and comparative physiology.

[57]  F. Marini,et al.  Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. , 2005, Cytotherapy.

[58]  A. Caplan.  Adult mesenchymal stem cells for tissue engineering versus regenerative medicine , 2007, Journal of cellular physiology.