Actions and therapeutic potential of stem cells

1. Actions and therapeutic potential of stem cells Dr. Simon R. Bailey BVMS PhD FHEA DipECVPT MRCVS Faculty of Veterinary Science, University of Melbourne, Victoria, Australia.

2. What happens when tissue gets injured, or just wears out? Immune cells come in and clear away the debris and any infection. Tissues can repair themselves, filling the void with tough but otherwise non-functional material : the scar. Regeneration is the complete restoration of the original tissue. Damaged tissue is replaced by new functional cells.

3. Injured tissues heal by a blend of repair and regeneration. > regeneration

4. Tissues regenerate new functional cells by: • either dividing the existing functional cells A stem cell must make more copies of itself (self-renew) and give rise to more capable offspring (differentiate). • or by activating an adult stem cell population.

5. What are stem cells?

6. What are stem cells?

7. Pluripotent or totipotent Difficult to obtain and grow Embryonic stem cells

8. Insertion of 3-4 genes into adult cells Induced pluripotent stem cells

9. Small numbers of cells, present in most tissues Capable of activation after injury Role in regeneration varies with tissue type Number declines with age Stem cells in the adult

10. The stem cell niche Maintains stem cells in a quiescent state

11. Mesenchymal Stem Cells (MSCs) Distinct group of stem cells Separate from haematopoietic stem cells, neural stem cells etc Part of the tissue stroma Self renewable Multipotent progenitor cells. Modified from Uccelli et al ,2008

12. Mesenchymal Stem Cells (MSCs) Modified from Chen and Tuanl ,2008

13. MSCs have been isolated from: bone marrow adipose tissue, lung, placenta, umbilical cord blood teeth (dental pulp) Bone marrow and adipose show most promising results Isolating mesenchymal stem cells for therapeutic use

14. Therapeutic use of adults stem cells Mainly preclinical trials Demonstrated effects in: cardiac tissues (post ischaemia) diabetes, osteoarthritis, tendon injury sepsis graft vs host disease

15. Therapeutic use of adults stem cells Mainly preclinical trials Demonstrated effects in: cardiac tissues (post ischaemia) diabetes, osteoarthritis, tendon injury sepsis graft vs host disease

16. Mesenchymal stem cells in arthritic diseases Trauma-induced large animal OA model (meniscus removal) 48 sheep (controlled, blinded) After 3 months: significantly greater thickness of joint cartilage, reduced cartilage breakdown, greater biomechanical strength compared with control joints receiving hyaluronic acid.

17. Actions of Mesenchymal Stem Cells (MSCs) MSCs have the ability to migrate to the sites of injury (express a variety of adhesion and chemokine receptors). Potential for tissue repair (Proliferation and matrix production) Potential for immunomodulatory effect (both innate and adaptive immunity)

18. The ability to differentiate into functional cells Provision of trophic support (via growth factors), Modulation of immune response and inflammation. Therapeutic actions of stem cells

19. Stem cell therapies tip the balance of healing more towards regeneration. Improved regeneration • Tissues resort to non-functional repair mechanisms when there is a lack of functional replacement cells • - either due to the properties of the tissue or the endogenous regeneration pathways being overwhelmed.

20. Trophic support Growth factors: TGFb Connective tissue growth factor VEGF BMP-2 (encourages development of bone and cartilage) Matrix production: GAG Therapeutic actions of stem cells

21. Potentially useful in: Inflammatory disease autoimmune disease graft vs host disease Immunomodulation by MSCs Modified from Uccelli et al ,2008

22. Immune modulation by mesenchymal stem cells Modified from Uccelli et al ,2008

23. Many examples of clear beneficial effects in laboratory species Early studies in humans Increasing evidence in veterinary species Evidence for therapeutic effects

24. Adipose-derived stem cells shown to be multipotent Vieira et al (2010) Cell Transplant. 19(3):279-89. 8. Significant improvements in chronic osteoarthritis of the hip joint, elbow joint. E.g. Gingerich et al (2007); Black et al (2008). Vet Therapeutics. Blinded and controlled studies undertaken Intervertebral disc repair With adipose-derived stem cells improved quality of regeneration. Ganey et al (2009) Spine 34(21):2297-304. Use of stem cells in the dog

25. Bone marrow derived and adipose-derived stem cells used Shown to differentiate into chondrocytes, osteocytes, myocytes in vitro Results in equine osteoarthritis equivocal (Frisbie and Smith, Equine Vet J 2010) Experimental models (Frisbie et al, 2009): Some improvement in inflammatory markers Prospective clinical study: 77% returned to work (Ferris et al, 2009) Very encouraging results for the treatment of tendinitis (Smith et al) Use of stem cells in the horse

26. The problem with tendinitis: Scar tissue (fibroplasia) replaces normal tendon tissue Impaired elasticity Effects of stem cell therapy: Improved quality of healing in collagenase tendinitis model(Crovace et al, 2010) Re-injury rate significantly lower (Smith 2008) Equine tendinitis and stem cells Crovace et al, 2010

27. Increasing understanding of how adult stem cells work Increasingly good evidence for clinical effects in common and important veterinary conditions Future directions: Optimising therapeutic potential Anti-inflammatory actions Intravenous delivery Conclusions

28. Any questions?