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are only a few that Nam ing Adipose-Derived Stem/ Stromal Cells There has been some variation and question regarding the correct terminology for stem/stromal adipose cells. At first, mesenchymal stem cells (discovered to have an active role in connective tissue repair in the early 1990s1 ) were thought to be the most important contributor to tissue regeneration; however, it became evident that within the adipose tissue complex is a key extracellular matrix, which included mature adipocytes and adipocytic precursors (known as progenitor cells). In addition, there was a variety of additional nucleated, undifferentiated, multipotent, and pluripotent cells, including pericytes and endothelial cells, which are all thought to play important roles in mesenchymal/ stromal-derived tissue regeneration (Figure 2). Therefore the term adipose-derived stem/stromal cells (AD-SCs), rather than simply “mesenchymal stem cell,” is used to describe this population of cells. Reference 1. Caplan A, Fink D, Goto T, et al. Mesenchymal stem cells and tissue repair. In Jackson DW (ed): The Anterior Cruciate Ligament: Current and Future Concepts. New York: Raven Press, 1993, p 405-417. Figure 2. Adipose tissue with (A) adipose cells, (B) extracellular matrix (most stem cells there), (C) pericytes (surround vessels; important in angiogenesis), (D) mesenchymal stem cells (small cells), and (E) pre-adipocytes (progenitor cells) July/August 2011 Today’s Veterinary Practice 25 Advances in Stem Cell Therapy | | Advances in Stem Cell Therapy 26 Today’s Veterinary Practice July/August 2011 are capable of consistently concentrating platelets to high-density therapeutic levels, including the Harvest Technologies Smart PReP2 centrifugation system (harvesttech.com), which has been cleared by the FDA. The Inflammatory Cascade Platelets contain a significant number of growth factors, key signal proteins, chemokines, cytokines, and other proinflammatory bioactive factors that initiate and regulate most basic aspects of the inflammatory cascade, resulting in natural wound healing (Table).37 • Elevated platelet concentrations are known to stimulate proliferation and differentiation, recruitment, and migration of mesenchymal and stromal repair cells to an injury site.38 • Circulating platelets, when activated, begin a degranulation process that secretes a variety of important growth factors and cytokines/chemokines.39 • Activated platelets also secrete stromal cell-derived factor 1 alpha (SDF-1a), which supports primary adhesion and migration of mesenchymal stem/stromal cells.40 Platelet’s Role in Wound Healing In many human stem/stromal cell protocols and some veterinary stem cell protocols, HDPRP is combined with AD-SC for placement into specific injury sites. There are also many examples of utilization of HDPRP, with and without stem/stromal cell additives, that have proven effective in acute and chronic full-thickness wound defects. Stimulation of the inflammatory cascade, coupled with the addition of AD-SC, remarkably shortens the healing process by promoting tissue regeneration (see Figure 3).41 RESEARCH Multiple studies, both in the human and veterinary literature, have clearly demonstrated the ability of AD-SCs to actively participate in tissue homeostasis, regeneration, and open wound healing.42-65 AD-SCs also differentiate into and repair musculoskeletal connective tissue, including: • Ligament • Tendon • Cartilage Figure 3. Use of high-density platelet-rich plasma in equine open wound defect: (A) Pre-operative avulsion, 4-degree tissue loss, bone surface exposed, wound 8 days old; (B) postoperative wound at 48 hours with 1 sharp debridement and thrombin-activated HDPRP topical concentrate; (C) postoperative wound on day 8 with 2 debridements plus second activated HDPRP topical concentrate; (D) split-thickness skin graft taken from left chest, suture fixed, and meshed, with activated HDPRP under graft and platelet-poor plasma as fibrin gel on surface. A B C D Table. Common Growth Factors Found in Platelet-Rich Plasma Fibroblast growth factor FGF Insulin-like growth factor IGF Interferons: Alpha, Gamma I-A, I-G Interleukin 1 IL-1 Platelet-derived angiogenesis factor PDAF Platelet-derived epidermal growth factor PDEGF Platelet-derived growth factor aa,bb,ab PDGF Platelet factor 4 PF-4 P-selectin GMP-140 Transforming growth factor B1, B2 TGF-B1, TGF-B2 July/August 2011 Today’s Veterinary Practice 27 Advances in Stem Cell Therapy | • Disk • Muscle • Nerve tissue • Bone • Hematopoietic-supporting stroma. In vitro, AD-SCs have demonstrated pluripotent capabilities to differentiate into a variety of nonmesodermally derived tissues, including hepatic, pancreatic, and keratocytic tissue, and to be effective in skin anti-aging and tissue regeneration, cardiovascular muscle and vascular tissue repair, rheumatoid arthritis, diabetes, and other diseases.66-75 For many years in human medicine, studies have focused on bone marrow-derived mesenchymal and hematopoietic undifferentiated cells. It is well documented that bone marrow possesses very few true mesenchymal stem cells, compared to AD-SCs, which are becoming the primary tissue source in clinical applications. Adipose is a complex cellular–vascular tissue that is not only easier to harvest, but offers markedly higher nucleated, undifferentiated stem cell counts than bone marrow.76
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