ISOLATION OF BONE MARROW MESENCHYMAL STEM CELLS EMBEDDED IN NATIVE TISSUE STROMA YIELDS ENRICHED HARVEST, IMPROVED ADHERENCE AND PROLIFERATION, AND UNIQUE SECRETOME
Main Article Content
Keywords
MSCs, bone marrow aspirate concentrate, orthobiologics, osteoarthritis
Abstract
Background: The field of orthobiologics traditionally utilizes cellular products, including bone-marrow aspirate concentrate (BMAC), micronized adipose tissue, and platelet preparations to address pain from degenerative processes, orthopedic injuries and medical conditions characterized by chronic inflammation and tissue degradation. For BMAC, maximizing the concentration of mesenchymal stem cells (MSCs) in a reduced volume is thought to allow for the therapeutic delivery of the cellular concentrate, secretome, and extracellular vesicles to a site of orthopedic injury or surgical repair. The extracellular matrix (ECM) within the bone marrow stroma contains collagens and proteoglycans known to regulate cell proliferation, migration, differentiation, and cell-cell communication among resident bone marrow cells. This study aimed to evaluate the cellular effects on MSC health and function when harvested to retain their native tissue stroma.
Methods: We evaluated a novel and unique processing method and device (BMAX™) to mechanically generate a purified MSC product derived from bone marrow in a nonenzymatic manner. BMAX™ products, including cells and stroma, were plated in MSC culture media and incubated for 3–14 days (P0-P1) before evaluation with flow cytometry for cell phenotyping and immunoassays for secretome profiling.
Results: The orthobiologic product containing three-dimensional stromal components can be produced in minutes using an automated bedside device requiring minimal benchtop space. We found increased MSC adherence, improved proliferative density in culture, and significantly elevated enrichment of stromal-derived MSCs versus traditional BMAC centrifugation-based preparations. Further, we demonstrate a unique secretome profile in BMAX™ versus traditional BMAC centrifugation-based preparations.
Conclusions: These qualities provide a novel and unique platform for autologous and allogeneic bone-marrow-derived therapy to better address inflammatory and destructive processes that may improve bone-marrow-derived cell therapies’ efficacy.
References
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23. Harford JS, Dekker TJ, Adams SB. Bone Marrow Aspirate Concentrate for Bone Healing in Foot and Ankle Surgery. Foot Ankle Clin. 2016;21(4):839-845.
24. Hegde V, Shonuga O, Ellis S, et al. A prospective comparison of 3 approved systems for autologous bone marrow concentration demonstrated nonequivalency in progenitor cell number and concentration. J Orthop Trauma. 2014;28(10):591-598.
25. Hernigou J, Picard L, Alves A, Silvera J, Homma Y, Hernigou P. Understanding bone safety zones during bone marrow aspiration from the iliac crest: the sector rule. Int Orthop. 2014;38(11):2377-2384.
26. Hernigou P, Homma Y, Flouzat Lachaniette CH, et al. Benefits of small volume and small syringe for bone marrow aspirations of mesenchymal stem cells. Int Orthop. 2013;37(11):2279-2287.
27. Hyer CF, Berlet GC, Bussewitz BW, Hankins T, Ziegler HL, Philbin TM. Quantitative assessment of the yield of osteoblastic connective tissue progenitors in bone marrow aspirate from the iliac crest, tibia, and calcaneus. J Bone Joint Surg Am. 2013;95(14):1312-1316.
28. Hynes RO. The Extracellular Matrix: Not Just Pretty Fibrils. Science (1979). 2009;326(5957):1216-1219.
29. Keeling LE, Belk JW, Kraeutler MJ, et al. Bone Marrow Aspirate Concentrate for the Treatment of Knee Osteoarthritis: A Systematic Review. Am J Sports Med. 2022;50(8):2315-2323.
30. Klamer S, Voermans C. The role of novel and known extracellular matrix and adhesion molecules in the homeostatic and regenerative bone marrow microenvironment. Cell Adh Migr. 2014;8(6):563-577.
31. Kraeutler MJ, Chahla J, LaPrade RF, Pascual-Garrido C. Biologic Options for Articular Cartilage Wear (Platelet-Rich Plasma, Stem Cells, Bone Marrow Aspirate Concentrate). Clin Sports Med. 2017;36(3):457-468.
32. Kumar R, Godavarthy PS, Krause DS. The bone marrow microenvironment in health and disease at a glance. J Cell Sci. 2018;131(4).
33. Lana JF, da Fonseca LF, Azzini G, et al. Bone Marrow Aspirate Matrix: A Convenient Ally in Regenerative Medicine. Int J Mol Sci. 2021;22(5).
34. Levy O, Mortensen LJ, Boquet G, et al. A small-molecule screen for enhanced homing of systemically infused cells. Cell Rep. 2015;10(8):1261-1268.
35. Li S, Cao P, Chen T, Ding C. Latest insights in disease-modifying osteoarthritis drugs development. Ther Adv Musculoskelet Dis. 2023;15:1759720X231169839.
36. Lin X, Patil S, Gao YG, Qian A. The Bone Extracellular Matrix in Bone Formation and Regeneration. Front Pharmacol. 2020;11.
37. Malemud CJ. Anticytokine therapy for osteoarthritis: evidence to date. Drugs Aging. 2010;27(2):95-115.
38. Di Matteo B, Vandenbulcke F, Vitale ND, et al. Minimally Manipulated Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis: A Systematic Review of Clinical Evidence. Stem Cells Int. 2019;2019:1735242.
39. Meszaros E, Malemud CJ. Prospects for treating osteoarthritis: enzyme-protein interactions regulating matrix metalloproteinase activity. Ther Adv Chronic Dis. 2012;3(5):219-229.
40. Pittenger MF, Discher DE, Péault BM, Phinney DG, Hare JM, Caplan AI. Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ Regen Med. 2019;4(1):22.
41. Pricola KL, Kuhn NZ, Haleem-Smith H, Song Y, Tuan RS. Interleukin-6 maintains bone marrow-derived mesenchymal stem cell stemness by an ERK1/2-dependent mechanism. J Cell Biochem. 2009;108(3):577-588.
42. Santos Duarte Lana JF, Furtado da Fonseca L, Mosaner T, et al. Bone marrow aspirate clot: A feasible orthobiologic. J Clin Orthop Trauma. 2020;11(Suppl 5):S789-S794.
43. Schäfer R, DeBaun MR, Fleck E, et al. Quantitation of progenitor cell populations and growth factors after bone marrow aspirate concentration. J Transl Med. 2019;17(1):115.
44. Schoch BS, Werner BC, Shapiro SA, Camp CL, Chalmers PN, Cancienne JM. Effect of Bone Marrow Aspirate Concentrate and Platelet-Rich Plasma Augmentation on the Rate of Revision Rotator Cuff Repair. Orthop J Sports Med. 2022;10(11):232596712211270.
45. Veronesi F, Giavaresi G, Tschon M, Borsari V, Nicoli Aldini N, Fini M. Clinical use of bone marrow, bone marrow concentrate, and expanded bone marrow mesenchymal stem cells in cartilage disease. Stem Cells Dev. 2013;22(2):181-192.
46. Wang S, Wei X, Zhou J, et al. Identification of α2-macroglobulin as a master inhibitor of cartilage-degrading factors that attenuates the progression of posttraumatic osteoarthritis. Arthritis Rheumatol. 2014;66(7):1843-1853.
47. Woodell-May J, Steckbeck K, King W. Potential Mechanism of Action of Current Point-of-Care Autologous Therapy Treatments for Osteoarthritis of the Knee-A Narrative Review. Int J Mol Sci. 2021;22(5).
48. Xing Z, Gauldie J, Cox G, et al. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest. 1998;101(2):311-320.
49. Zanetti C, Krause DS. “Caught in the net”: the extracellular matrix of the bone marrow in normal hematopoiesis and leukemia. Exp Hematol. 2020;89:13-25.
50. Zhang R, Ma J, Han J, Zhang W, Ma J. Mesenchymal stem cell related therapies for cartilage lesions and osteoarthritis. Am J Transl Res. 2019;11(10):6275-6289.
51. Ziegler CG, Van Sloun R, Gonzalez S, Whitney KE, DePhillipo NN, Kennedy MI, Dornan GJ, Evans TA, Huard J, LaPrade RF. Characterization of Growth Factors, Cytokines, and Chemokines in Bone Marrow Concentrate and Platelet-Rich Plasma: A Prospective Analysis. Am J Sports Med. 2019;47(9):2174-2187.
2. Auw Yang KG, Raijmakers NJH, van Arkel ERA, et al. Autologous interleukin-1 receptor antagonist improves function and symptoms in osteoarthritis when compared to placebo in a prospective randomized controlled trial. Osteoarthritis Cartilage. 2008;16(4):498-505.
3. Birbrair A, Frenette PS. Niche heterogeneity in the bone marrow. Ann N Y Acad Sci. 2016;1370(1):82-96.
4. Bogers SH. Cell-Based Therapies for Joint Disease in Veterinary Medicine: What We Have Learned and What We Need to Know. Front Vet Sci. 2018;5:70.
5. Caplan AI. Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol. 2007;213(2):341-347.
6. Cavallo C, Boffa A, Andriolo L, et al. Bone marrow concentrate injections for the treatment of osteoarthritis: evidence from preclinical findings to the clinical application. Int Orthop. 2021;45(2):525-538.
7. Chahla J, Dean CS, Moatshe G, Pascual-Garrido C, Serra Cruz R, LaPrade RF. Concentrated Bone Marrow Aspirate for the Treatment of Chondral Injuries and Osteoarthritis of the Knee: A Systematic Review of Outcomes. Orthop J Sports Med. 2016;4(1):2325967115625481.
8. Chahla J, Mannava S, Cinque ME, Geeslin AG, Codina D, LaPrade RF. Bone Marrow Aspirate Concentrate Harvesting and Processing Technique. Arthrosc Tech. 2017;6(2):e441-e445.
9. Choi H, Lee RH, Bazhanov N, Oh JY, Prockop DJ. Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-κB signaling in resident macrophages. Blood. 2011;118(2):330-338.
10. Chu W, Zhuang Y, Gan Y, Wang X, Tang T, Dai K. Comparison and characterization of enriched mesenchymal stem cells obtained by the repeated filtration of autologous bone marrow through porous biomaterials. J Transl Med. 2019;17(1):377.
11. Coutu DL, Kokkaliaris KD, Kunz L, Schroeder T. Three-dimensional map of nonhematopoietic bone and bone-marrow cells and molecules. Nat Biotechnol. 2017;35(12):1202-1210.
12. Domingues MJ, Cao H, Heazlewood SY, Cao B, Nilsson SK. Niche Extracellular Matrix Components and Their Influence on HSC. J Cell Biochem. 2017;118(8):1984-1993.
13. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-317.
14. Dregalla RC, Herrera JA, Donner EJ. Red blood cells and their releasates compromise bone marrow-derived human mesenchymal stem/stromal cell survival in vitro. Stem Cell Res Ther. 2021;12(1):547.
15. Dregalla RC, Herrera JA, Koldewyn LS, Donner EJ. The Choice of Anticoagulant Influences the Characteristics of Bone Marrow Aspirate Concentrate and Mesenchymal Stem Cell Bioactivity In Vitro. Stem Cells Int. 2022;2022:8259888.
16. Drela K, Stanaszek L, Snioch K, et al. Bone marrow-derived from the human femoral shaft as a new source of mesenchymal stem/stromal cells: an alternative cell material for banking and clinical transplantation. Stem Cell Res Ther. 2020;11(1):262.
17. El-Kadiry AEH, Lumbao C, Rafei M, Shammaa R. Autologous BMAC Therapy Improves Spinal Degenerative Joint Disease in Lower Back Pain Patients. Front Med (Lausanne). 2021;8:622573.
18. Everts PA, Malanga GA, Paul R V., Rothenberg JB, Stephens N, Mautner KR. Assessing clinical implications and perspectives of the pathophysiological effects of erythrocytes and plasma free hemoglobin in autologous biologics for use in musculoskeletal regenerative medicine therapies. A review. Regen Ther. 2019;11:56-64.
19. Glenn R, Johns W, Walley K, Jackson JB, Gonzalez T. Topical Review: Bone Marrow Aspirate Concentrate and Its Clinical Use in Foot and Ankle Surgery. Foot Ankle Int. 2021;42(9):1205-1211.
20. Gobbi A, Karnatzikos G, Scotti C, Mahajan V, Mazzucco L, Grigolo B. One-Step Cartilage Repair with Bone Marrow Aspirate Concentrated Cells and Collagen Matrix in Full-Thickness Knee Cartilage Lesions: Results at 2-Year Follow-up. Cartilage. 2011;2(3):286-299.
21. Grunke M, Schulze-Koops H. Successful treatment of inflammatory knee osteoarthritis with tumour necrosis factor blockade. Ann Rheum Dis. 2006;65(4):555-556.
22. Haines CM, Bhatt FR, Orosz LD, et al. Low Back Pain, Disability, and Quality of Life One Year following Intradiscal Injection of Autologous Bone Marrow Aspirate Concentrate. Stem Cells Int. 2022;2022:9617511.
23. Harford JS, Dekker TJ, Adams SB. Bone Marrow Aspirate Concentrate for Bone Healing in Foot and Ankle Surgery. Foot Ankle Clin. 2016;21(4):839-845.
24. Hegde V, Shonuga O, Ellis S, et al. A prospective comparison of 3 approved systems for autologous bone marrow concentration demonstrated nonequivalency in progenitor cell number and concentration. J Orthop Trauma. 2014;28(10):591-598.
25. Hernigou J, Picard L, Alves A, Silvera J, Homma Y, Hernigou P. Understanding bone safety zones during bone marrow aspiration from the iliac crest: the sector rule. Int Orthop. 2014;38(11):2377-2384.
26. Hernigou P, Homma Y, Flouzat Lachaniette CH, et al. Benefits of small volume and small syringe for bone marrow aspirations of mesenchymal stem cells. Int Orthop. 2013;37(11):2279-2287.
27. Hyer CF, Berlet GC, Bussewitz BW, Hankins T, Ziegler HL, Philbin TM. Quantitative assessment of the yield of osteoblastic connective tissue progenitors in bone marrow aspirate from the iliac crest, tibia, and calcaneus. J Bone Joint Surg Am. 2013;95(14):1312-1316.
28. Hynes RO. The Extracellular Matrix: Not Just Pretty Fibrils. Science (1979). 2009;326(5957):1216-1219.
29. Keeling LE, Belk JW, Kraeutler MJ, et al. Bone Marrow Aspirate Concentrate for the Treatment of Knee Osteoarthritis: A Systematic Review. Am J Sports Med. 2022;50(8):2315-2323.
30. Klamer S, Voermans C. The role of novel and known extracellular matrix and adhesion molecules in the homeostatic and regenerative bone marrow microenvironment. Cell Adh Migr. 2014;8(6):563-577.
31. Kraeutler MJ, Chahla J, LaPrade RF, Pascual-Garrido C. Biologic Options for Articular Cartilage Wear (Platelet-Rich Plasma, Stem Cells, Bone Marrow Aspirate Concentrate). Clin Sports Med. 2017;36(3):457-468.
32. Kumar R, Godavarthy PS, Krause DS. The bone marrow microenvironment in health and disease at a glance. J Cell Sci. 2018;131(4).
33. Lana JF, da Fonseca LF, Azzini G, et al. Bone Marrow Aspirate Matrix: A Convenient Ally in Regenerative Medicine. Int J Mol Sci. 2021;22(5).
34. Levy O, Mortensen LJ, Boquet G, et al. A small-molecule screen for enhanced homing of systemically infused cells. Cell Rep. 2015;10(8):1261-1268.
35. Li S, Cao P, Chen T, Ding C. Latest insights in disease-modifying osteoarthritis drugs development. Ther Adv Musculoskelet Dis. 2023;15:1759720X231169839.
36. Lin X, Patil S, Gao YG, Qian A. The Bone Extracellular Matrix in Bone Formation and Regeneration. Front Pharmacol. 2020;11.
37. Malemud CJ. Anticytokine therapy for osteoarthritis: evidence to date. Drugs Aging. 2010;27(2):95-115.
38. Di Matteo B, Vandenbulcke F, Vitale ND, et al. Minimally Manipulated Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis: A Systematic Review of Clinical Evidence. Stem Cells Int. 2019;2019:1735242.
39. Meszaros E, Malemud CJ. Prospects for treating osteoarthritis: enzyme-protein interactions regulating matrix metalloproteinase activity. Ther Adv Chronic Dis. 2012;3(5):219-229.
40. Pittenger MF, Discher DE, Péault BM, Phinney DG, Hare JM, Caplan AI. Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ Regen Med. 2019;4(1):22.
41. Pricola KL, Kuhn NZ, Haleem-Smith H, Song Y, Tuan RS. Interleukin-6 maintains bone marrow-derived mesenchymal stem cell stemness by an ERK1/2-dependent mechanism. J Cell Biochem. 2009;108(3):577-588.
42. Santos Duarte Lana JF, Furtado da Fonseca L, Mosaner T, et al. Bone marrow aspirate clot: A feasible orthobiologic. J Clin Orthop Trauma. 2020;11(Suppl 5):S789-S794.
43. Schäfer R, DeBaun MR, Fleck E, et al. Quantitation of progenitor cell populations and growth factors after bone marrow aspirate concentration. J Transl Med. 2019;17(1):115.
44. Schoch BS, Werner BC, Shapiro SA, Camp CL, Chalmers PN, Cancienne JM. Effect of Bone Marrow Aspirate Concentrate and Platelet-Rich Plasma Augmentation on the Rate of Revision Rotator Cuff Repair. Orthop J Sports Med. 2022;10(11):232596712211270.
45. Veronesi F, Giavaresi G, Tschon M, Borsari V, Nicoli Aldini N, Fini M. Clinical use of bone marrow, bone marrow concentrate, and expanded bone marrow mesenchymal stem cells in cartilage disease. Stem Cells Dev. 2013;22(2):181-192.
46. Wang S, Wei X, Zhou J, et al. Identification of α2-macroglobulin as a master inhibitor of cartilage-degrading factors that attenuates the progression of posttraumatic osteoarthritis. Arthritis Rheumatol. 2014;66(7):1843-1853.
47. Woodell-May J, Steckbeck K, King W. Potential Mechanism of Action of Current Point-of-Care Autologous Therapy Treatments for Osteoarthritis of the Knee-A Narrative Review. Int J Mol Sci. 2021;22(5).
48. Xing Z, Gauldie J, Cox G, et al. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest. 1998;101(2):311-320.
49. Zanetti C, Krause DS. “Caught in the net”: the extracellular matrix of the bone marrow in normal hematopoiesis and leukemia. Exp Hematol. 2020;89:13-25.
50. Zhang R, Ma J, Han J, Zhang W, Ma J. Mesenchymal stem cell related therapies for cartilage lesions and osteoarthritis. Am J Transl Res. 2019;11(10):6275-6289.
51. Ziegler CG, Van Sloun R, Gonzalez S, Whitney KE, DePhillipo NN, Kennedy MI, Dornan GJ, Evans TA, Huard J, LaPrade RF. Characterization of Growth Factors, Cytokines, and Chemokines in Bone Marrow Concentrate and Platelet-Rich Plasma: A Prospective Analysis. Am J Sports Med. 2019;47(9):2174-2187.
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Apr 24, 2024
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Dregalla , R., Herrera, J., Koldewyn, L., Hambright, S., Donner, C., Singer, J., Donner, J., & Huard, J. (2024). ISOLATION OF BONE MARROW MESENCHYMAL STEM CELLS EMBEDDED IN NATIVE TISSUE STROMA YIELDS ENRICHED HARVEST, IMPROVED ADHERENCE AND PROLIFERATION, AND UNIQUE SECRETOME. Biologic Orthopedics Journal, 6(1), 7–20. https://doi.org/10.22374/boj.v6i1.61
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