IN 1909, Alexander Maximow, a
Russian academic, introduced the
concept of “multipotent” blood
stem cells when he addressed the
Berlin Haematologic Society.
Decades later, in 1976, another
Russian, Alexander, Friedenstein, was
investigating haematopoietic stem
cells in mice when he discovered a
population of cells
harvested from bone
marrow that were
adherent to culture
vessels, mesenchymal
(fibroblast-like) and
colony forming with high replicative
capacity (Friedenstein et al, 1976).
These cells became known as
“mesenchymal stem cells” (MSCs). As
well as their discovery, Friedenstein is
credited with foresight into the
clinical application of MSCs,
particularly in the field of
orthopaedics.
He performed detailed studies
with Gabriel Ilazarov, who any
budding orthopaedist will recognise as
a pioneer of external fixation and
limb-lengthening methods. MSCs are
currently in clinical veterinary use for
fracture management, osteoarthritis
(OA) and tendon injury.
The defining characteristics of an
MSC are those
of self-renewal (the ability to
go through
numerous cycles
of cell division
whilst
maintaining
their
undifferentiated
state), and of multipotency (the ability to generate
progeny of several distinct cell types).
MSCs offer potential as they have
the property of multipotency, but
with fewer ethical considerations than
embryo-derived stem cells. In fact, the
scientific and public interest has
grown exponentially.
Figure 1 illustrates the number of papers published in each of the last
20 years that show up in a PubMed
search for “mesenchymal stem cells”:
60 in 1993; 5,118 in 2013.
A surge in interest also followed
the discovery, made in 2002, that
MSCs could be derived from adipose
tissue (Zuk et al, 2002), the harvest of
which is easier and associated with
less morbidity than that of bone
marrow. The extraction of MSCs
from fat and their expansion is now
commercially available to vets in the
UK via The Veterinary Tissue Bank.
Extraction-only services are also
advertised for MSC isolation. These
services are quicker as they do not
require the expansion of MSCs.
However, the extraction process
yields a heterogeneous population of
cells called the stromal vascular
fraction (SVF).
Only an estimated 1 to 10% of
the SVF are actually MSCs (Mitchell et
al, 2006; Oedayrajsingh-Varma et al,
2006; Zhu et al, 2008).
Bone healing
A canine fracture gap model has been
used to demonstrate beneficial effects
of autogenous (Bruder et al, 1998)
and allogeneic (Arinzeh et al, 2003)
MSCs on bone healing.
In 2007 Bajada and colleagues,
from the Robert Jones and Agnes
Hunt Orthopaedic Hospital in
Oswestry, reported the successful
management of a tibial fracture in a
man that had been refractory to six
attempts at surgical management over
a nine-year period. Calcium sulphate
pellets combined with cultured,
autogenous, bone marrow-derived
MSCs were implanted.
However, as the
expansion (culture) of
MSCs takes approximately
two weeks, MSCs are
unlikely to replace
autogenous bone graft, or
off-the-shelf
osteoinductive products
such as demineralised bone
matrix (DBM) or
recombinant human bone morphogeneic proteins
(rhBMP), in the
management of routine
fractures. They might,
however, prove useful
in planned revision
surgeries of non-
unions.
The authors are
aware of an unpublished case of
autogenous MSCs being
used to successfully
treat a delayed union in
the tibia of a cat.
Osteoarthritis
The therapeutic
rationale for MSCs is a shifting
paradigm. The original hypothesis was
that MSCs, or other stem cells, could
be injected or implanted, either
systemically or locally, into a patient,
and that the cells would find their way to the damaged tissue, differentiate
into the needed
cell-type, and
assist repair.
Indeed, a
current trend in
cartilage defect
treatment is the
implantation of
stem cells, often
on a synthetic
scaffold, with the
aim of tissue
regeneration
(Emadedin et al,
2012; Haleem et al,
2010;
Kasemkijwattana
et al, 2011).
However, it is increasingly
recognised that MSCs may have
modes of action that are paracrine in
nature. That is, they may alter the
environment of a diseased tissue or
organ, such that reparative processes
are augmented.
In a caprine model of OA
(involving complete excision of the
medial meniscus and resection of
the cranial cruciate ligament) a
single injection of an expanded
population of autogenous bone
marrow-derived MSCs resulted in
reduced cartilage degradation,
osteophytosis and sub-chondral sclerosis compared to
controls.
Yet, there was no
evidence of MSC
engraftment in the
cartilage of the treated
joints, engraftment
was only high in the
synovium, fat pad and
lateral meniscus
(Murphy et al, 2003).
Tendon injury
In equine orthopaedics there is
considerable interest in the use of
MSCs to treat tendon injury.
In a tendon gap model, using
rabbits’ Achilles tendons, MSC treated tendons had better
mechanical properties than
operated controls (Young et
al, 1998). Re-injury rate of
National Hunt horses with
overstrain injuries of the
superficial digital flexor
tendon treated with
intralesional MSC injections
have been reported as
25.7%, which is significantly
lower than those treated by
other methods (Godwin et
al, 2011).
Summary
Interest in MSCs is set to continue. In small animal
orthopaedics at least, perhaps the most promising application is in the
treatment of joint disease.
Anecdotal reports of response to
intra-articular injections of MSCs for
the management of OA are
encouraging. It is anticipated that
reports concerning the safety and
efficacy of MSCs will be forthcoming
in the near future.
References
The full list of references is available
on request to editor@veterinary-
practice.com.
