the concepts vet-stem credentialing course veterinary regenerative medicine 101
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The Concepts Vet-Stem Credentialing Course Veterinary Regenerative Medicine 101. Regenerative Medicine. What should you ask about any new therapy?. Evidence of potential mechanisms Evidence of efficacy Evidence of safety Formulary for how to use in practice. Course Outline. - PowerPoint PPT PresentationTRANSCRIPT
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The ConceptsVet-Stem Credentialing CourseVeterinary Regenerative Medicine 101
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Evidence of potential mechanisms Evidence of efficacy Evidence of safety Formulary for how to use in practice
Regenerative Medicine
What should you ask about any new therapy?
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VRM 101 The ConceptsVRM 102 Evidence-Based Regenerative Medicine –
Pain and Orthopedic UseVRM 103 Stem Cell Mediated RegenerationVRM 104A Small Animal Clinician’s ApproachVRM 104B Equine Clinician’s ApproachVRM 105A Small Animal Adipose Harvest / InjectionVRM 105B Equine Adipose Harvest / Injection
Course Outline
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Discover the meaning of “Regenerative Medicine” Stem Cells – What really are they? Learn the sources and types of stem cells Explore the mechanisms of action of stem cells
Regenerative Medicine
Module Outline
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What is Regenerative Medicine?
10 million cells die in your body every minute of every day.
Your own stem cells replace them so you can continue living.
Goal of Regenerative Medicine:
Restitutio In IntegrumRestore to Original
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Regenerative MedicineDamage Repair
Regenerate
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Why Use Regenerative Medicine?
Current research and clinical trials are exploring regenerative medicine for nearly every organ system. Examples are:
OsteoarthritisTendon/ligament injuryRenal failureLiver failureLaminitisImmune-mediated diseases: atopy, IBD, COPD
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Slide 8
What are Stem Cells?
Pericytes on blood vessels. Courtesy Arnold Caplan and
Bruno Peault
Stem Cells are:
– Primitive cells present in almost every tissue
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What are Stem Cells?
Stem Cells are:
– Primitive cells present in almost every tissue
– Able to become different types of tissue:
Tendon, Ligament, Bone
Stem cells differentiated into cardiomyocytes using growth factors. Courtesy
NIH.
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What are Stem Cells?
Stem Cells are:
– Primitive cells present in almost every tissue
– Able to become different types of tissue:
Tendon, Ligament, Bone
Stem cells differentiated into cardiomyocytes using growth factors. Courtesy
NIH.
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What are Stem Cells?
Dividing stem cells. Courtesy Salk Institute.
Stem Cells are:
– Primitive cells present in almost every tissue
– Able to become different types of tissue:
Tendon, Ligament, Bone
– Self-renewing
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What are Stem Cells?
Stem Cells are:
– Primitive cells present in almost every tissue
– Able to become different types of tissue:
Tendon, Ligament, Bone
– Self-renewing– Pharmaceutical
Factories
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Definitions
Multipotent turn into any cell line of same germ layerPluripotent turn into any cell line except placentalTotipotent turn into any cell type including placental
Autograft from animal A, into animal AAllograft from animal B, into animal AXenograft from species B, into species A
Mesenchymal originating from mesoderm
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A Rose By Any Other Name
Stem cells aka…
Mesenchymal stem cellsMesenchymal Stromal cellsMultipotent / Pluripotent cellsStromal vascular fractionNucleated fraction
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Embryonic vs Adult Stem Cells
Embryonic Source: early embryo
ethical dilemma
Differentiate into all tissues
Purpose: form organism
Form Teratomas UNPREDICTABLE
Adult Source: all adult tissues (?)
no ethical dilemma
Differentiate into most tissues
Purpose: Regenerate
No evidence of Teratoma formation
Gruen L and Grabel L, Concise Review: “Scientific and Ethical Roadblocks to Human Embryonic Stem Cell Therapy.” Stem Cell 2006;24;2162-2169.
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How to Use Stem Cells
Caplan, J Cell. Physiol. 2007, 213: 341-347
Cell Therapy Injection of non-
differentiated cells Cells coordinate healing
and regeneration
NOW
Tissue Engineering Growing tissues and/or organs ex-
vivo Stem cells differentiated on a
scaffold then implanted
Potential Future
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Stem Cell Mediated Regeneration
1. Homing (like WBC)
2. Differentiationa. Direct differentiation into needed cell types
b. Recruit and stimulate mitosis of local progenitor cells
3. Trophic support - growth factors and cytokinesa. Block pain (opioid receptor agonist)
b. Down-regulate inflammatory mediators
c. Block cell death (anti-apoptosis)
d. Stimulate angiogenesis
e. Anti-fibrosis (block scar)
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Homing Mechanism – Fracture Model
Homing of luminescent adipose stem cells to fracture site from IV administration.
S-W Lee et al, J Ortho Res, 2009(Stanford Univ)
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Cruciate Ligament - Chondroprotection
Toghraie et al, “Treatment of osteoarthritis with infrapatellar fat pad derived mesenchymal stem cells in rabbit” The Knee 2011;1:71-75.
Sham Surgery ASC IA Control
Above toluidine blue staining of cartilage surface at 20 weeks after cranial cruciate ligament transection. Only treatment was group B given 1MM adipose-stem cells by intraarticular injection with no carrier/scaffold.
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Slide 20
Eaton M. Cell and molecular approaches to the attenuation of pain after spinal cord injury. J Neurotrauma 2006;23(23/4):549-59. Guo – Bone marrow stromal cells produce long-term pain relief in rat models of persistent pain. Stem Cells 2011;29(8):1294-1303.
Klass M, Gavrikov V, Csete M et al. Intravenous mononuclear marrow cells reverse neuropathic pain from experimental mononeuropathy. Anesth Analg 2007;104:944-948. Malik RA, Veves A, Tesfaye S. Ameliorating human diabetic neuropathy: Lessons from implanting hematopoietic mononuclear cells. Exper Neuro 2006; 201:7-14. Takagi K, Okuda-Ashitaka E, Ito S et al. Involvement of stem cell factor and its receptor tyrosine kinase c-kit in pain regulation. Neurosci 2008;153:1278-88.
Pain Relief Mechanisms
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Model – ligation of masseter muscle nerve (constriction injury)
Pain Relief Mechanisms
Guo et al, Stem Cells 2011;29(8):1294-1303.
Normal
Highly Sensitized
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Anti-inflammation / Anti-fibrosis
Co-staining of IL1-RA (red) protein and subpopulation of MSCs (DAPI, blue).
Ortiz et al, PNAS 2007.(Tulane Univ)
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Mechanisms of RegenerationDifferentiation into tissue
(Photo courtesy Cytori Therapeutics)
Nerve
Bone
Cartilage
Liver
Fat-derivedStem Cells
Cardiac
Fat
Angiogensis/Anti-apoptosis
Gene Therapy
Muscle
Reviewed in: Tobita M. Adipose-derived stem cells: current findings and future perspectives. Disc Med 2011;11(57):160-170.
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Mechanisms of RegenerationStimulation of MSC Proliferation
Kol et al (UCD). EVJ 2012.
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Mechanisms of RegenerationStimulation of MSC Migration
Kol et al (UCD). EVJ 2012.
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Cartilage Regeneration Model
Dragoo J et al, “Healing full-thickness cartilage defects using adipose-derived stem cells” Tiss Eng 2007;13(7):1615-21. (Stanford)
At 8 weeks, 12/12 (100%) of defects in treated group healing with hyaline-like cartilage. Only 1/12 (8%) of controls healed.
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Slide 27
Anti-apoptosis Mechanism
Untreated Control ADSC IA Treated Group
Leu et al, J Translational Med 2010;8(63).
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Anti-fibrosis Mechanism
Mouse Liver Fibrosis – CCl4 – BM-MSC IV Infusions1. Decrease TGF-B (decrease response of stellate cells)2. Increase IL-10 (antifibrogenic cytokine)
Fang et al, Transplantation 78:1;2004
Control MSC
Blue = fibrosis
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Homing and Angiogenesis
Ischemia Model – Adipose Cell Therapy7 days post ischemia - IV
Laser Doppler Blood Flow
Saline Control
Adipose StemCell Treated
Miranville, Circulation, 2004
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Slide 30
Roles / Functions
“Stem cells are injury-specific, perfectly choreographed pharmaceutical factories”
Influenced by injury micro-environment
“Paramedics”
Dr. Arnold Caplan, Case Western Reserve University
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‘Activation’ of Stem Cells
“In vivo use of hMSCs for therapeutic indications does not require priming of MSCs.”
Annu. Rev. Pathol. Mech. Dis. 2011. 6:457–78
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1. Goal of Regenerative Medicine is to return damaged tissue to normal state.
2. Regenerative cells function by:- Homing- Differentiation into needed tissues- Trophic stimulation of regeneration
3. Activation of stem cells is not necessary for therapeutic effects, and may be harmful.
Summary - Regenerative Medicine