Comparative Efficacy of Autologous Stromal Vascular Fraction and Autologous Adipose-Derived Mesenchymal Stem Cells Combined With Hyaluronic Acid for the Treatment of Sheep Osteoarthritis

Abstract

The current study explored whether intra-articular (IA) injection of autologous adipose mesenchymal stem cells (ASCs) combined with hyaluronic acid (HA) achieved better therapeutic efficacy than autologous stromal vascular fraction (SVF) combined with HA to prevent osteoarthritis (OA) progression and determined how long autologous ASCs combined with HA must remain in the joint to observe efficacy. OA models were established by performing anterior cruciate ligament transection (ACLT) and medial meniscectomy (MM). Autologous SVF (1×107 mononuclear cells), autologous low-dose ASCs (1×107), and autologous high-dose ASCs (5×107) combined with HA, and HA alone, or saline alone were injected into the OA model animals at 12 and 15 weeks after surgery, respectively. Compared with SVF+HA treatment, low-dose ASC+HA treatment yielded better magnetic resonance imaging (MRI) scores and macroscopic results, while the cartilage thickness of the tibial plateau did not differ between low, high ASC+HA and SVF+HA treatments detected by micro-computed tomography (µCT). Immunohistochemistry revealed that high-dose ASC+HA treatment rescued hypertrophic chondrocytes expressing collagen X in the deep area of articular cartilage. Western blotting analysis indicated the high- and low-dose ASC+HA groups expressed more collagen X than did the SVF+HA group. Enzyme-linked immunosorbent assay showed treatment with both ASC+HA and SVF+HA resulted in differing anti-inflammatory and trophic effects. Moreover, superparamagnetic iron oxide particle (SPIO)-labeled autologous ASC signals were detected by MRI at 2 and 18 weeks post-injection and were found in the lateral meniscus at 2 weeks and in the marrow cavity of the femoral condyle at 18 weeks post-injection. Thus, IA injection of autologous ASC+HA may demonstrate better efficacy than autologous SVF+HA in blocking OA progression and promoting cartilage regeneration, and autologous ASCs (5×107 cells) combined with HA potentially survive for at least 18 weeks after IA injection.

Injectable Systems for Intra-Articular Delivery of Mesenchymal Stromal Cells for Cartilage Treatment: A Systematic Review of Preclinical and Clinical Evidence

“…HA has also been employed to inject bone marrow-derived MSCs in focal defects, promoting enhanced cartilage repair in minipigs [ 40 ], goats [ 41 ], horses [ 42 ], and rabbits [ 43 ] relative to control treatments including HA alone or cells without HA. Similarly, improved cartilage repair and reduced disease progression and inflammation were documented in animal models of OA treated with HA and bone marrow- or adipose tissue-derived MSCs in goats and sheep [ 44 , 45 , 46 ], donkeys [ 47 ], pigs [ 48 ], rabbits [ 34 , 49 ], and rats [ 50 ] versus HA alone or cells without HA. Overall, only four [ 34 , 43 , 48 , 50 ] out of these studies directly compared the use of MSCs with or without HA, and among these, three demonstrated the benefits of using the cell carrier combination with respect to MSCs alone, while one study described better results in counteracting OA progression using MSCs and HA alone compared with their combination [ 50 ].…”

“…Similarly, in MSCs and HA combination, preclinical results are overall positive in both animal models of focal and degenerative lesions, in particular in terms of the reduction of inflammation and disease progression [ 34 , 44 , 45 , 46 , 47 , 48 , 49 ]. In the clinical settings, all papers described the treatment of osteochondral lesions, showing safety and positive results and the regeneration of hyaline-like cartilage over the same protocol without cells [ 66 ].…”

Stem Cell Treatment for Knee Articular Cartilage Defects and Osteoarthritis

“…Knee degeneration can also be induced in animals through surgical means, such as iatrogenic anterior cruciate ligament transection [25], meniscectomy [26], osteochondral fragmentation [27], or tibial plateau fracture [28]. Studies have included and ranged from small animal models such as rats and rabbits to large animal models such as sheep, pigs, and dogs [26,[29][30][31][32].…”

“…Injectables in animal models have often included adjuvants such as platelet-rich plasma (PRP) [31,32,38] and hyaluronic acid (HA) [27,29], which theoretically may promote cell proliferation, type II collagen synthesis, and inflammatory chemotaxis synergistically. In a dog OA model, Yun et al found that cotreatment with injectable MSCs and PRP showed greater improvement in extracellular matrix composition, focal compression strength, and glycosaminoglycan and collagen composition than those treated with PRP or MSCs alone in comparison with sham controls [31].Similarly, Chiang et al found that cotreatment with MSCs/HA resulted in better histological scores and cartilage content in comparison with HA alone, attributable to engraftment of allogenic MSCs in surface cartilage [27].…”

In Vitro Cultures of Adipose-Derived Stem Cells: An Overview of Methods, Molecular Analyses, and Clinical Applications

“…Multiple studies have tried to evaluate the influence of ASC intra-articular injection and intravenous infusion on osteoarthritis treatment outcomes. It has been proven that the administration of ASCs could reduce pain and lameness, suppress the local inflammation, improve mobility and activity, and potentially promote cartilage regeneration [77][78][79][80][81].…”