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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.
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.
Injured tissues heal by a blend of repair and regeneration.
> regeneration
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.
What are stem cells?
What are stem cells?
Embryonic stem cells
• Pluripotent or
totipotent
• Difficult to obtain
and grow
Induced pluripotent stem cells
• Insertion of 3-4 genes into adult cells
Stem cells in the adult
• Small numbers of
cells, present in most
tissues
• Capable of activation
after injury
• Role in regeneration
varies with tissue type
• Number declines with
age
The stem cell niche
Maintains stem cells
in a quiescent state
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
Mesenchymal Stem Cells (MSCs)
Modified from Chen and Tuanl ,2008
Isolating mesenchymal stem cells for
therapeutic use
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
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
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
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.
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)
Therapeutic actions of stem cells
• The ability to differentiate into functional
cells
• Provision of trophic support
– (via growth factors),
• Modulation of immune response and
inflammation.
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.
Stem cell therapies
tip the balance of
healing more towards
regeneration.
Therapeutic actions of stem cells
Trophic support
• Growth factors:
– TGFb
– Connective tissue growth factor
– VEGF
– BMP-2 (encourages development of bone and cartilage)
• Matrix production:
– GAG
Immunomodulation by MSCs
Potentially useful in:
• Inflammatory disease
• autoimmune disease
• graft vs host disease
Modified from Uccelli et al ,2008
Immune modulation by mesenchymal stem cells
Modified from Uccelli et al ,2008
Evidence for therapeutic effects
• Many examples of clear beneficial effects
in laboratory species
• Early studies in humans
• Increasing evidence in veterinary species
Use of stem cells in the dog
• 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 horse
• 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)
Equine tendinitis and stem cells
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)
Crovace et al, 2010
Conclusions
• 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
Any questions?