Effect of Extracorporeal Shock Wave Therapy on Equine Umbilical Cord Blood Mesenchymal Stromal Cells in vitro by Ramés

EFECT OF EXTRACORPOREAL SHOCK WAVE THERAPY ON EQUINE UMBILICAL CORD BLOOD MESENCHYMAL STROMAL CELLS IN VITRO Ramés II Salcedo Jiménez Advisors: University of Guelph, 2019 Dr. Judith Koenig Dr. Thomas G Koch Extracorporeal shock wave therapy (ESWT) has been shown to induce different biological effects on a variety of cells, including regulation and stimulation of their function and metabolism. ESWT can promote different biological responses such as proliferation, migration, and regenerations of cells. Recent studies have shown that mesenchymal stromal cells (MSCs) secrete factors that enhance regeneration of tissues, stimulate proliferation and differentiation of cells and decrease inflammatory and immune-reactions. Clinically, the combination of these two therapies has been used as treatment for tendon and ligament lesions in horses; however, there is no scientific evidence supporting this combination of therapies in vivo. Therefore, the objectives of the study were to evaluate if ESWT affects equine umbilical cord blood mesenchymal stromal cells (CBMSCs) proliferative, metabolic, migrative, differentiation, and immunomodulatory properties in vitro. Equine CB-MSCs were treated using an electrohydraulic shock wave generator attached to a water bath. All experiments were performed as triplicates. Proliferation, viability, migration and immunomodulatory properties of the cells were evaluated. Equine CB-MSCs were induced to evaluate their trilineage differentiation potential. ESWT treated cells had increased metabolic activity, showed positive adipogenic, osteogenic, and chondrogenic differentiation, and showed higher potential for differentiation towards the adipogenic and osteogenic cell fates. ESWT treated cells showed similar immunomodulatory properties to non-ESWT treated cells. Equine CB-MSCs are sensitive to ESWT treatment and showed increased metabolic, adipogenic and osteogenic activity, but unaltered immunosuppressive properties. In vivo studies are warranted to determine if synergistic effects can be obtained in the treatment musculoskeletal injuries if ESWT and equine CB-MSC therapies are combined.

[1]  Xunbo Jin,et al.  A promising therapeutic option for diabetic bladder dysfunction: Adipose tissue‐derived stem cells pretreated by defocused low‐energy shock wave , 2019, Journal of tissue engineering and regenerative medicine.

[2]  J. Denoix,et al.  Intra-Articular Injection of 2 Different Dosages of Autologous and Allogeneic Bone Marrow- and Umbilical Cord-Derived Mesenchymal Stem Cells Triggers a Variable Inflammatory Response of the Fetlock Joint on 12 Sound Experimental Horses , 2019, Stem cells international.

[3]  M. S. Kallos,et al.  Improved expansion of equine cord blood derived mesenchymal stromal cells by using microcarriers in stirred suspension bioreactors , 2019, Journal of Biological Engineering.

[4]  J. Spaas,et al.  Equine Allogeneic Chondrogenic Induced Mesenchymal Stem Cells Are an Effective Treatment for Degenerative Joint Disease in Horses , 2019, Stem cells and development.

[5]  T. Koch,et al.  Equine Cord Blood Mesenchymal Stromal Cells Have Greater Differentiation and Similar Immunosuppressive Potential to Cord Tissue Mesenchymal Stromal Cells. , 2019, Stem cells and development.

[6]  K. Ortved.  Regenerative Medicine and Rehabilitation for Tendinous and Ligamentous Injuries in Sport Horses. , 2018, The Veterinary clinics of North America. Equine practice.

[7]  Sophie H Bogers,et al.  Cell-Based Therapies for Joint Disease in Veterinary Medicine: What We Have Learned and What We Need to Know , 2018, Front. Vet. Sci..

[8]  B. Christ,et al.  Cellular and Molecular Mechanisms of Mesenchymal Stem Cell Actions , 2017, Stem cells international.

[9]  R. van Weeren,et al.  Effect of single intralesional treatment of surgically induced equine superficial digital flexor tendon core lesions with adipose-derived mesenchymal stromal cells: a controlled experimental trial , 2017, Stem Cell Research & Therapy.

[10]  S. Sharif,et al.  Equine allogeneic umbilical cord blood derived mesenchymal stromal cells reduce synovial fluid nucleated cell count and induce mild self-limiting inflammation when evaluated in an lipopolysaccharide induced synovitis model. , 2016, Equine veterinary journal.

[11]  Kenta Ito,et al.  Molecular mechanisms of the angiogenic effects of low-energy shock wave therapy: roles of mechanotransduction. , 2016, American journal of physiology. Cell physiology.

[12]  Carl A. Gregory,et al.  Mechanisms of mesenchymal stem/stromal cell function , 2016, Stem Cell Research & Therapy.

[13]  G. Chamberlain,et al.  A review of the cellular and molecular effects of extracorporeal shockwave therapy , 2016, Veterinary and Comparative Orthopaedics and Traumatology.

[14]  F. Marano,et al.  Extracorporeal shock waves modulate myofibroblast differentiation of adipose‐derived stem cells , 2016, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[15]  M. C. d'Agostino,et al.  Shock wave as biological therapeutic tool: From mechanical stimulation to recovery and healing, through mechanotransduction. , 2015, International journal of surgery.

[16]  Yun Xu,et al.  Human umbilical cord mesenchymal stem cells: an overview of their potential in cell-based therapy , 2015, Expert opinion on biological therapy.

[17]  D. Bienzle,et al.  Phenotypic and Immunomodulatory Properties of Equine Cord Blood-Derived Mesenchymal Stromal Cells , 2015, PloS one.

[18]  Rajarshi Pal,et al.  Allogeneic and autologous mode of stem cell transplantation in regenerative medicine: which way to go? , 2014, Medical hypotheses.

[19]  C. Schuh,et al.  In vitro extracorporeal shock wave treatment enhances stemness and preserves multipotency of rat and human adipose-derived stem cells. , 2014, Cytotherapy.

[20]  Yaron Mazor,et al.  Cell-based therapy approaches: the hope for incurable diseases. , 2014, Regenerative medicine.

[21]  J. Holfeld,et al.  Shock wave application to cell cultures. , 2014, Journal of visualized experiments : JoVE.

[22]  J. Greve,et al.  Clinical follow-up of horses treated with allogeneic equine mesenchymal stem cells derived from umbilical cord blood for different tendon and ligament disorders , 2014, The Veterinary quarterly.

[23]  C. Kawcak,et al.  Clinical outcome after intra-articular administration of bone marrow derived mesenchymal stem cells in 33 horses with stifle injury. , 2014, Veterinary surgery : VS.

[24]  J. Rompe,et al.  Clinical application of shock wave therapy (SWT) in musculoskeletal disorders. , 2014, European journal of physical and rehabilitation medicine.

[25]  W. Bloch,et al.  Cell biological effects of mechanical stimulations generated by focused extracorporeal shock wave applications on cultured human bone marrow stromal cells. , 2013, Stem cell research.

[26]  Chenyu Huang,et al.  Mechanotherapy: revisiting physical therapy and recruiting mechanobiology for a new era in medicine. , 2013, Trends in molecular medicine.

[27]  Jun-Gu Kang,et al.  Characterization and clinical application of mesenchymal stem cells from equine umbilical cord blood , 2013, Journal of veterinary science.

[28]  G. Scheiner-Bobis,et al.  Effect of extracorporeal shock wave on proliferation and differentiation of equine adipose tissue-derived mesenchymal stem cells in vitro. , 2013, American journal of stem cells.

[29]  K. Braeckmans,et al.  In search for cross‐reactivity to immunophenotype equine mesenchymal stromal cells by multicolor flow cytometry , 2012, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[30]  D. Frisbie,et al.  Cell-based therapies for equine joint disease. , 2011, The Veterinary clinics of North America. Equine practice.

[31]  Chun-Jen Huang,et al.  Extracorporeal shock wave accelerates consolidation in distraction osteogenesis of the rat mandible. , 2010, The Journal of trauma.

[32]  T. Parkin,et al.  An investigation of the relationship between race performance and superficial digital flexor tendonitis in the Thoroughbred racehorse. , 2010, Equine veterinary journal.

[33]  Yanjun Zeng,et al.  Shockwaves increase T-cell proliferation and IL-2 expression through ATP release, P2X7 receptors, and FAK activation. , 2010, American journal of physiology. Cell physiology.

[34]  H. Birch,et al.  A review of tendon injury: why is the equine superficial digital flexor tendon most at risk? , 2010, Equine veterinary journal.

[35]  S. Dyson,et al.  Medical management of superficial digital flexor tendonitis: a comparative study in 219 horses (1992-2000). , 2010, Equine veterinary journal.

[36]  C. Kawcak,et al.  Evaluation of adipose‐derived stromal vascular fraction or bone marrow‐derived mesenchymal stem cells for treatment of osteoarthritis , 2009, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[37]  Marjolein C H van der Meulen,et al.  Mesenchymal stem cells and insulin‐like growth factor‐I gene‐enhanced mesenchymal stem cells improve structural aspects of healing in equine flexor digitorum superficialis tendons , 2009, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[38]  B. Bryan,et al.  The function of vascular endothelial growth factor , 2009, BioFactors.

[39]  Feng-Sheng Wang,et al.  The effects of shockwave on bone healing and systemic concentrations of nitric oxide (NO), TGF-beta1, VEGF and BMP-2 in long bone non-unions. , 2009, Nitric oxide : biology and chemistry.

[40]  U. Ritz,et al.  Extracorporeal shock wave-mediated changes in proliferation, differentiation, and gene expression of human osteoblasts. , 2008, The Journal of trauma.

[41]  M. Cotrufo,et al.  Shock waves activate in vitro cultured progenitors and precursors of cardiac cell lineages from the human heart. , 2008, Ultrasound in medicine & biology.

[42]  T. Sasho,et al.  Extracorporeal shock wave therapy improves motor dysfunction and pain originating from knee osteoarthritis in rats. , 2007, Osteoarthritis and cartilage.

[43]  P. Thomsen,et al.  Isolation of mesenchymal stem cells from equine umbilical cord blood , 2007, BMC biotechnology.

[44]  S. Ohtori,et al.  Extracorporeal shockwaves induce the expression of ATF3 and GAP-43 in rat dorsal root ganglion neurons , 2006, Autonomic Neuroscience.

[45]  D. Ingber,et al.  Cellular mechanotransduction: putting all the pieces together again , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[46]  R. Evans,et al.  Evaluation of analgesia resulting from extracorporeal shock wave therapy and radial pressure wave therapy in the limbs of horses and sheep. , 2005, American journal of veterinary research.

[47]  Kailash,et al.  Shock wave treatment in medicine , 2005, Journal of Biosciences.

[48]  Yeung-Jen Chen,et al.  Extracorporeal shock waves promote healing of collagenase‐induced Achilles tendinitis and increase TGF‐β1 and IGF‐I expression , 2004, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[49]  Yeung-Jen Chen,et al.  Activation of extracellular signal-regulated kinase (ERK) and p38 kinase in shock wave-promoted bone formation of segmental defect in rats. , 2004, Bone.

[50]  S. McClure,et al.  Extracorporeal shock wave therapy: Clinical applications and regulation , 2003 .

[51]  Stefan Wagenpfeil,et al.  Extracorporeal shock wave therapy for the treatment of chronic calcifying tendonitis of the rotator cuff: a randomized controlled trial. , 2003, JAMA.

[52]  J. Ogden,et al.  Principles of shock wave therapy. , 2001, Clinical orthopaedics and related research.

[53]  M. Nieswand,et al.  Review: The use of shock waves in medicine—a tool of the modern OR: An overview of basic physical principles, history and research , 2000, Minimally invasive therapy & allied technologies : MITAT : official journal of the Society for Minimally Invasive Therapy.

[54]  G. Haupt.  Use of extracorporeal shock waves in the treatment of pseudarthrosis, tendinopathy and other orthopedic diseases. , 1997, The Journal of urology.

[55]  S. Meloche,et al.  Inhibition of Growth Factor-induced Protein Synthesis by a Selective MEK Inhibitor in Aortic Smooth Muscle Cells* , 1996, The Journal of Biological Chemistry.

[56]  E. Schmiedt,et al.  EXTRACORPOREALLY INDUCED DESTRUCTION OF KIDNEY STONES BY SHOCK WAVES , 1980, The Lancet.

[57]  Amarpal,et al.  Equine Mesenchymal Stem Cells: Properties, Sources, Characterization, and Potential Therapeutic Applications , 2019, Journal of equine veterinary science.

[58]  J. Dudhia,et al.  Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon. , 2012, Equine veterinary journal.

[59]  N. Chutkan,et al.  Extracorporeal shock wave therapy for the treatment of lateral epicondylitis. , 2011, Orthopedics.

[60]  L. Xiang,et al.  Mesenchymal stem cells: a promising candidate in regenerative medicine. , 2008, The international journal of biochemistry & cell biology.

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

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

[63]  K. Weitkamp,et al.  Radial Extracorporeal Shock Wave Therapy for Chronic Insertion Desmopathy of the Proximal Suspensory Ligament , 2000 .

[64]  S. McClure,et al.  Extracorporeal Shock Wave Therapy for Treatment of Osteoarthritis of the Tarsometatarsal and Distal Intertarsal Joints of the Horse , 2000 .