What is VetStem Regenerative Medicine?
Regenerative Medicineis a broad definition for innovative medical therapies that will enable the body to repair, replace, restore, and regenerate damaged or diseased tissues.
VetStem Regenerative Medicineuses a concentrated form of autologous adipose-derived adult stem cells to treat traumatic and degenerative diseases, including bowed tendons, ligament injuries, osteoarthritis, and osteochondral defects in horses, dogs, and cats.
DEMONSTRATED EFFICACY OF REGENERATIVE CELL THERAPY
Human clinical trials:
Ongoing human clinical trials:
- Advanced heart failure
- Heart bypass surgical trial
- Liver disease
- Renal disease
Animal models of disease:
Success in human clinical trials and animal models
Despite its relative infancy, regenerative medicine is not new. Success in numerous animal models of disease and emerging success in human clinical trials for Crohn's fistulas1 and stroke,2 along with hundreds of ongoing clinical trials (see sidebar) support the rationale for stem cell use, and now success, in veterinary medicine. VetStem collaborative and clinical research demonstrate positive results in treating horses with tendon and ligament injuries, osteochondral defects, and osteoarthritis.3-6 The first peer-reviewed double-blinded multicenter study for adipose-derived stem cell therapy use in canine osteoarthritis of the hip showed significant improvement in all post treatment evaluation times for lameness, pain, and range of motion. Similar results have been obtained for canine elbows and stifles.
Stem cells are multipotent and can differentiate into tendon, ligament, bone, cartilage, cardiac, nerve, muscle, blood vessels, fat, and liver tissue22,23 (see figure below). The stromal fraction that is harvested from adipose tissue is a heterogeneous mixture of regenerative cells (see below).
Stem cells are harvested from the animal
Harvested cells are a heterogeneous mixture of cells with many functions
VetStem Technology: Summary
VetStem Regenerative Cell Therapy is based on a clinical technology licensed from Artecel Inc. Original patents are from the University of Pittsburgh and Duke University.
- Rationale based on consistent therapeutic success in numerous animal models of disease (see sidebar)
- Adipose-derived stem cells (VetStem Regenerative Cells: VSRC™)
- Autologous cell therapy
- Currently used in horses with bowed tendons, ligament injuries, and joint disease
- Currently used in dogs and cats for osteoarthritis and soft tissue injuries
- Over 14,000 animals treated
- Reported canine adverse reaction rate is 0.1%
- Reported equine adverse reaction rate is 0.2%
- Reported feline adverse reaction rate is 0.3%
- Demonstrated efficacy with VSRC™ therapy in horses and dogs
- Cornell University double-blinded, placebo controlled study5
- Retrospective studies3,4,37
- Case studies6
- Double-blinded placebo controlled multicenter study
Why use adipose-derived regenerative cells rather than regenerative cells derived from bone marrow?
Adipose-derived regenerative cells are:
- Readily available source
- Stem cells can be collected in far greater numbers from adipose than from bone marrow24
- Able to differentiate into multiple lineages implicating their potential in bone, cartilage, and cardiac repair23
- Fractions isolated from adipose tissue contain a heterogeneous mixture of
regenerative cells, including:23
- Mesenchymal stem cells (MSCs)
- Endothelial progenitor cells
- Immune cells
- Other growth factor-secreting bioactive cells
Differences in Regenerative Medicine compared to traditional medicine:
- Regenerative Cell Therapy does not rely on a single target receptor or a single pathway for its action
- Regenerative cell mixture is delivered either directly to the traumatic wound (e.g.: tendonitis, desmitis, fracture) or are delivered systemically (e.g.: renal disease, inflammatory bowel disease, gingivostomatitis)
- Regenerative cells can differentiate into many tissue types, induce repair, and stimulate regeneration22
- Regenerative cells "communicate" with the cells of their local environment through paracrine and autocrine modalities, creating the optimal environment for natural healing25
- Regenerative cells produce a variety of both secreted and cell surface substances that regulate tissue growth, integrity, and function25
Mechanisms for success:
VetStem Regenerative Cell (VSRC™) therapy delivers a functionally diverse cell population able to communicate with other cells in their local environment. Until recently, differentiation was thought to be the primary function of regenerative cells. However, the functions of regenerative cells are now known to be much more diverse and are implicated in a highly integrated and complex network. VSRC™ therapy should be viewed as a complex, yet balanced, approach to a therapeutic goal. Unlike traditional medicine, in which one drug targets one receptor, Regenerative Medicine, including VSRC™ therapy, can be applied in a wide variety of traumatic and developmental diseases. Regenerative cell functions include:
In general, in vitro studies demonstrate that MSCs limit inflammatory responses and promote anti-inflammatory pathways.
- When present in an inflammatory environment, data demonstrates that MSCs may alter the cytokine secretion profile of dendritic cell (DC) subsets and T-cell subsets causing a shift from a pro-inflammatory environment to an anti-inflammatory or tolerant environment.26
- MSCs do not express MHC class II antigens or costimulatory molecules and they suppress T-cell proliferation.29
- MSCs suppress mixed lymphocyte reactions and inhibit T-cell proliferation induced by a third cell type or by mitogenic factors.29
- MSCs are able to control lethal graft versus host disease (GVHD) in mice after haploidentical hematopoietic transplantation.29-30
Multiple studies demonstrate that MSCs secrete bioactive levels of cytokines and growth factors that support angiogenesis, tissue remodeling, differentiation, and antiapoptotic events.25,28 MSCs secrete a number of angiogenesis-related cytokines such as:28
- Vascular endothelial growth factor (VEGF)
- Hepatocyte growth factor (HGF)
- Basic fibroblast growth factor (bFGF)
- Granulocyte-macrophage colony stimulating factor (GM-CSF)
- Transforming growth factor (TGB) – β
Adipose-derived MSC studies demonstrate a diverse plasticity, including differentiation into adipo-, osteo-, chondro-, myo-, cardiomyo-, endothelial, hepato-, neuro-, epithelial, and hematopoietic lineages, similar to that described for bone marrow derived MSCs.22 These data are supported by in vivo experiments and functional studies that demonstrated the regenerative capacity of adipose-derived MSCs to repair damaged or diseased tissue via transplant engraftment and differentiation.6,9,30
- Awad and colleagues reported significant improvements using autologous MSC delivery in a rabbit Achilles tendon repair model compared to cell-free collagen control rabbits.9
- Nixon and colleagues demonstrated statistically significant improvement in histological repair of a collagenase-induced injury in the superficial digital flexor tendon in horses treated with autologous regenerative cells harvested from fat.5
- In a caprine model of traumatic joint injury, MSCs delivered intra-articularly engrafted and repaired meniscal tissue, leading to a statistically significant reduction in the progression of osteoarthritis.7
- Multiple studies demonstrate in vivo bone regeneration and repair in animal models. Bruder and colleagues demonstrated in two studies that MSCs could be used to repair a critical defect in a non-union fracture model in dogs.10,11
- Cowan and colleagues demonstrated that MSCs heal a critical-size mouse calvarial defect in which there was increased bone formation and mineralization compared to controls.12
- A human clinical case showed a dramatic regeneration of the calvarium in a young girl with severe traumatic damage.31
- In a rodent cerebral infarct model, Jeong and colleagues demonstrated that infarcted rats administered magnetically labeled MSCs two weeks after the creation of an infarct experienced a higher success rate of restoration of locomotor function compared to controls.13
Homing (chemotaxis) is an event by which a cell migrates from one area of the body to a distant site where it may be needed for a given physiological event. Homing is an important function of MSCs and other progenitor cells and one mechanism by which intravenous or parenteral administration of MSCs permits an auto-transplanted therapeutic cell to effectively target a specific area of pathology.
- Nilsson and colleagues demonstrated that labeled cells of bone lineage injected intravenously into mice can engraft, form bone, and give rise to osteocytes and bone lining cells detectable on the mouse femur.32
- Chen and colleagues performed peripheral intravenous experiments using a cerebral arterial occlusion model of stroke and demonstrated that labeled MSCs administered 24 hours and 7 days post-injury migrated to the area of injury and dramatically reduced stroke infarct size.14
Adipose-derived regenerative cells contain endothelial progenitor cells and MSCs that assist in angiogenesis and neovascularization by the secretion of cytokines, such as hepatic growth factor (HGF), vascular endothelial growth factor (VEGF), placental growth factor (PGF), transforming growth factor (TGFβ), fibroblast growth factor (FGF-2), and angiopoietin.25
- Chen and colleagues examined the effect of intravenous administration of MSCs after cerebral arterial occlusion in the rat and demonstrated new capillary formation, increased vessel formation and increased VEGF (vascular endothelial growth factor) expression in the areas of the lesion.33
- In an in vivo model of hind limb eschemia, intravenous injection of MSCs were associated with an increase in blood flow and capillary density and incorporation of the cells in the leg vasculature.34
- Rehman and colleagues reported that nude mice with ischemic hind limbs treated with MSCs demonstrated marked perfusion improvement.28
Apoptosis is defined as a programmed cell death or “cell suicide”, an event that is genetically controlled.35 Under normal conditions, apoptosis determines the lifespan and coordinated removal of cells. Unlike during necrosis, apoptotic cells are typically intact during their removal (phagocytosis).
- Rehman and colleagues demonstrated this effect in acutely injured tissue denied critical blood-flow resulting in ischemia. MSCs significantly reduced endothelial cell apoptosis.28
- Kortesidis and colleagues also demonstrated that MSCs express factors that support cell survival and avoid apoptosis thereby preserving cells that would otherwise be destroyed.36