Accepted Manuscript Title: Stem cell therapy in the horse: From laboratory to clinic Author: Catharina De Schauwer PII: DOI: Reference:
S1090-0233(14)00531-0 http://dx.doi.org/doi: 10.1016/j.tvjl.2014.12.033 YTVJL 4381
To appear in:
The Veterinary Journal
Please cite this article as: Catharina De Schauwer, Stem cell therapy in the horse: From laboratory to clinic, The Veterinary Journal (2015), http://dx.doi.org/doi: 10.1016/j.tvjl.2014.12.033. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Guest Editorial
2 3
Stem cell therapy in the horse: From laboratory to clinic
4 5
The therapeutic use of equine mesenchymal stem cells (MSCs) for orthopaedic
6
injuries was first reported in 2003, at which time there were less than five peer-reviewed
7
research articles published on the topic (Borjesson and Peroni, 2011). Since then, the clinical
8
use of MSCs has increased exponentially, with thousands of horses now being treated
9
worldwide. Although fundamental research in the area has also expanded, it substantially lags
10
behind premature product development and clinical experimentation using this methodology.
11
As eloquently highlighted in a review paper by Deanne Whitworth and Tania Banks from The
12
School of Veterinary Science at the University of Queensland, Australia, in a recent issue of
13
The Veterinary Journal, the question remains whether MSC-based therapies are fit for
14
purpose in mainstream equine veterinary practice (Whitworth and Banks, 2014).
15 16
Many fundamental questions remain regarding the clinical application of MSCs in
17
veterinary medicine. These include the efficacy and timing of these treatments, the
18
appropriate or optimum dose of cells to administer in particular clinical settings, the route of
19
administration, whether or not additional scaffolding is required and whether the MSCs used
20
are autologous or allogeneic (Borjesson and Peroni, 2011; Fortier and Travis, 2011;
21
Whitworth and Banks, 2014). Most equine clinical studies report on the use of bone marrow-
22
derived MSCs that have been expanded in vitro prior to use. This provides a degree of quality
23
control and creates the expectation that the effect of treatment is actually due to the MSCs. On
24
the other hand, cell suspensions containing mixtures of cells can also be administered
25
immediately without an in vitro expansion step, which reduces in vitro selection pressure on
Page 1 of 3
26
the cells and is less time-consuming (Koch et al., 2009). It is not yet known how many MSCs
27
are present in these non-expanded suspensions or if a critical number of MSCs is required to
28
induce tissue regeneration (Whitworth and Banks, 2014). So far, almost no dose-response
29
studies have been performed (Fortier and Travis, 2011).
30 31
In general, most cell-based therapies use autologous MSCs. Considering their
32
immunosuppressive properties, the use of allogeneic MSC may have advantages in providing
33
an ‘off-the-shelf’, standardised and readily available product without the inherent lag period
34
associated with isolation and expansion of autologous MSCs (De Schauwer et al., 2014).
35
However, inherent differences exist between MSCs from different tissues and, as such, MSCs
36
derived from neonatal sources are preferred from an immunomodulatory perspective based on
37
their higher proliferative capacity and lower immunogenicity relative to adult derived MSCs
38
(Deuse et al., 2011; De Schauwer et al., 2014).
39 40
There remains a marked disparity between the presumptive benefits of MSC therapy
41
and their proven abilities as defined by rigorously controlled scientific studies. It should be
42
highlighted that, in human medicine, many additional steps beyond in vitro characterisation
43
must be undertaken before a cell-based therapy is used in human patients. In contrast, in
44
veterinary medicine, stem cell therapies are not rigorously regulated (Koch et al., 2009) and
45
are administered without demonstrating appropriate efficacy either in vitro or in pre-clinical
46
studies (Fortier and Travis, 2011). The efficacy of MSC therapy has been difficult to evaluate
47
to date because appropriate control groups are not always included and MSCs are often
48
combined with potential confounding factors, such as bone marrow supernatant, autologous
49
serum and platelet-rich plasma (Koch et al., 2009). Therefore, the current literature frequently
50
relies on studies that are often not designed to the gold standards of evidence-based medicine,
Page 2 of 3
51
i.e. double blinded, randomised control trials, as highlighted in the review by Whitworth and
52
Banks (2014). In conclusion, there is an urgent need to demonstrate the true efficacy of these
53
treatments by establishing clinical trials which include sufficient and similar cases and with
54
consistent, objective and quantifiable outcomes.
55 56 57 58 59 60 61 62
Catharina De Schauwer Reproductive Biology Unit Department of Reproduction, Obstetrics and Herd Health, Faculty of Veterinary Medicine, Ghent University, Belgium E-mail address: [email protected]
63
References
64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86
Borjesson, D.L., Peroni, J.F., 2011. The regenerative medicine laboratory: Facilitating stem cell therapy for equine disease. Journal of Laboratory and Clinical Medicine 31, 109123. De Schauwer, C., Goossens, K., Piepers, S., Hoogewijs, M.K., Govaere, J.L., Smits, K., Meyer, E., Van Soom, A., Van de Walle, G.R., 2014. Characterization and profiling of immunomodulatory genes of equine mesenchymal stromal cells from noninvasive sources. Stem Cell Research and Therapy 5, 6. Deuse, T., Stubbendorff, M., Tang-Quan, K., Philips, N., Kay, M.A., Eiermann. T., Phan, T.T., Volk, H.D., Reichenspurner, H., Robbins, R.C., et al., 2011. Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells. Cell Transplant 20, 655-667. Fortier, L.A., Travis, A.J., 2011. Stem cells in veterinary medicine. Stem Cell Research Therapy 2, 9. Koch, T.G., Berg, L.C., Betts, D.H., 2009. Current and future regenerative medicine principles, concepts, and therapeutic use of stem cell therapy and tissue engineering in equine medicine. Canadian Veterinary Journal 50, 155-165. Whitworth, D.J., Banks, T.A., 2014. Stem cell therapies for treating osteoarthritis: Prescient or premature? The Veterinary Journal 202, 416-424.
Page 3 of 3
S1090-0233(14)00531-0 http://dx.doi.org/doi: 10.1016/j.tvjl.2014.12.033 YTVJL 4381
To appear in:
The Veterinary Journal
Please cite this article as: Catharina De Schauwer, Stem cell therapy in the horse: From laboratory to clinic, The Veterinary Journal (2015), http://dx.doi.org/doi: 10.1016/j.tvjl.2014.12.033. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Guest Editorial
2 3
Stem cell therapy in the horse: From laboratory to clinic
4 5
The therapeutic use of equine mesenchymal stem cells (MSCs) for orthopaedic
6
injuries was first reported in 2003, at which time there were less than five peer-reviewed
7
research articles published on the topic (Borjesson and Peroni, 2011). Since then, the clinical
8
use of MSCs has increased exponentially, with thousands of horses now being treated
9
worldwide. Although fundamental research in the area has also expanded, it substantially lags
10
behind premature product development and clinical experimentation using this methodology.
11
As eloquently highlighted in a review paper by Deanne Whitworth and Tania Banks from The
12
School of Veterinary Science at the University of Queensland, Australia, in a recent issue of
13
The Veterinary Journal, the question remains whether MSC-based therapies are fit for
14
purpose in mainstream equine veterinary practice (Whitworth and Banks, 2014).
15 16
Many fundamental questions remain regarding the clinical application of MSCs in
17
veterinary medicine. These include the efficacy and timing of these treatments, the
18
appropriate or optimum dose of cells to administer in particular clinical settings, the route of
19
administration, whether or not additional scaffolding is required and whether the MSCs used
20
are autologous or allogeneic (Borjesson and Peroni, 2011; Fortier and Travis, 2011;
21
Whitworth and Banks, 2014). Most equine clinical studies report on the use of bone marrow-
22
derived MSCs that have been expanded in vitro prior to use. This provides a degree of quality
23
control and creates the expectation that the effect of treatment is actually due to the MSCs. On
24
the other hand, cell suspensions containing mixtures of cells can also be administered
25
immediately without an in vitro expansion step, which reduces in vitro selection pressure on
Page 1 of 3
26
the cells and is less time-consuming (Koch et al., 2009). It is not yet known how many MSCs
27
are present in these non-expanded suspensions or if a critical number of MSCs is required to
28
induce tissue regeneration (Whitworth and Banks, 2014). So far, almost no dose-response
29
studies have been performed (Fortier and Travis, 2011).
30 31
In general, most cell-based therapies use autologous MSCs. Considering their
32
immunosuppressive properties, the use of allogeneic MSC may have advantages in providing
33
an ‘off-the-shelf’, standardised and readily available product without the inherent lag period
34
associated with isolation and expansion of autologous MSCs (De Schauwer et al., 2014).
35
However, inherent differences exist between MSCs from different tissues and, as such, MSCs
36
derived from neonatal sources are preferred from an immunomodulatory perspective based on
37
their higher proliferative capacity and lower immunogenicity relative to adult derived MSCs
38
(Deuse et al., 2011; De Schauwer et al., 2014).
39 40
There remains a marked disparity between the presumptive benefits of MSC therapy
41
and their proven abilities as defined by rigorously controlled scientific studies. It should be
42
highlighted that, in human medicine, many additional steps beyond in vitro characterisation
43
must be undertaken before a cell-based therapy is used in human patients. In contrast, in
44
veterinary medicine, stem cell therapies are not rigorously regulated (Koch et al., 2009) and
45
are administered without demonstrating appropriate efficacy either in vitro or in pre-clinical
46
studies (Fortier and Travis, 2011). The efficacy of MSC therapy has been difficult to evaluate
47
to date because appropriate control groups are not always included and MSCs are often
48
combined with potential confounding factors, such as bone marrow supernatant, autologous
49
serum and platelet-rich plasma (Koch et al., 2009). Therefore, the current literature frequently
50
relies on studies that are often not designed to the gold standards of evidence-based medicine,
Page 2 of 3
51
i.e. double blinded, randomised control trials, as highlighted in the review by Whitworth and
52
Banks (2014). In conclusion, there is an urgent need to demonstrate the true efficacy of these
53
treatments by establishing clinical trials which include sufficient and similar cases and with
54
consistent, objective and quantifiable outcomes.
55 56 57 58 59 60 61 62
Catharina De Schauwer Reproductive Biology Unit Department of Reproduction, Obstetrics and Herd Health, Faculty of Veterinary Medicine, Ghent University, Belgium E-mail address: [email protected]
63
References
64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86
Borjesson, D.L., Peroni, J.F., 2011. The regenerative medicine laboratory: Facilitating stem cell therapy for equine disease. Journal of Laboratory and Clinical Medicine 31, 109123. De Schauwer, C., Goossens, K., Piepers, S., Hoogewijs, M.K., Govaere, J.L., Smits, K., Meyer, E., Van Soom, A., Van de Walle, G.R., 2014. Characterization and profiling of immunomodulatory genes of equine mesenchymal stromal cells from noninvasive sources. Stem Cell Research and Therapy 5, 6. Deuse, T., Stubbendorff, M., Tang-Quan, K., Philips, N., Kay, M.A., Eiermann. T., Phan, T.T., Volk, H.D., Reichenspurner, H., Robbins, R.C., et al., 2011. Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells. Cell Transplant 20, 655-667. Fortier, L.A., Travis, A.J., 2011. Stem cells in veterinary medicine. Stem Cell Research Therapy 2, 9. Koch, T.G., Berg, L.C., Betts, D.H., 2009. Current and future regenerative medicine principles, concepts, and therapeutic use of stem cell therapy and tissue engineering in equine medicine. Canadian Veterinary Journal 50, 155-165. Whitworth, D.J., Banks, T.A., 2014. Stem cell therapies for treating osteoarthritis: Prescient or premature? The Veterinary Journal 202, 416-424.
Page 3 of 3
