Erythrocyte removal from bone marrow aspirate concentrate improves efficacy as intra-articular cellular therapy in a rodent osteoarthritis model

Abstract

Background: Despite the high prevalence of osteoarthritis (OA), there remains a need for additional therapeutic options. Cellular therapies with minimally manipulated cells such as bone marrow aspirate concentrates (BMAC) are increasingly popular in the U.S. but clear-cut evidence of efficacy has not been established. In theory, BMAC injections provide a source of stromal cells to stimulate healing in OA and ligamentous injuries; however, BMAC injections are also often associated with inflammation, short-term pain, and mobility impairment. Given that blood is known to trigger inflammation in joints, we hypothesized that removing erythrocytes [red blood cells (RBCs)] from BMAC preparations prior to intra-articular injection would improve efficacy for OA treatment.; Methods: To test this hypothesis, BMAC was collected from the bone marrow of mice. Three treatment groups were pursued: (I) untreated; (II) BMAC; or (III) BMAC depleted of RBCs by lysis. Product was injected into the femorotibial joint of mice 7 days after OA had been induced by destabilization of the medial meniscus (DMM). To assess the impact of treatment on joint function, individual cage monitoring (ANY-maze TM ) and Digigait treadmill-based analyses were performed over 4 weeks. At study completion, joint histopathology was assessed and immune transcriptomes within joint tissues were compared using a species-specific NanoString panel.; Results: Significant improvements in activity, gait parameters, and histology scores were seen in animals receiving RBC-depleted BMAC compared to untreated mice; animals treated with non-depleted BMAC did not demonstrate this same extent of consistent significant improvement. Transcriptomic analysis of joint tissues revealed significant upregulation of key anti-inflammatory genes, including interleukin-1 receptor antagonist (IRAP), in mice treated with RBC-depleted BMAC compared to animals treated with non-RBC depleted BMAC.; Conclusions: These findings indicate that RBC depletion in BMAC prior to intra-articular injection improves treatment efficacy and reduces joint inflammation compared to BMAC.; Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-4256/coif). LMP reports that support for this work was provided by Animal Health and Disease (No. 19HMFPXXXXG039150001) from the USDA National Institute of Food and Agriculture, Carolyn Quan and Porter Bennett, NIH/NCATS CTSA 5TL1TR002533-02, NIH 5T32OD010437-19, and Colorado State University Veterinary Summer Scholars Program USDA Animal Health and Disease Fellowship. LMP reports that a provisional patent has been filed covering the fractionated bone marrow aspirate product described herein. LMP serves as a member of the advisory team for EqCell Inc., and has stock options in EqCell Inc. LC reports that a provisional patent has been filed covering the fractionated bone marrow aspirate product described herein. SD reports that a provisional patent has been filed covering the fractionated bone marrow aspirate product described herein and that he is a cofounder (without revenue) of a virtual startup company developing an unrelated cellular therapeutic product for treatment of chronic wound infections. The other authors have no conflicts of interest to declare. (2023 Annals of Translational Medicine. All rights reserved.)