Rest in Peace Arnie

Published on Jan 13, 2024

This week the field of regenerative medicine lost a true luminary and the founder of the field, Arnold Caplan, Ph.D. professor at Case Western, passed away peacefully on January 10th at the age of 80. Today I would like to honor this man who changed so many lives for the better.

The GOAT

The term GOAT is often thrown around, but if the field of regenerative medicine were to bestow that honor on anyone, it would be Arnie Caplan. Why? Because Arnie literally discovered MSCs and orthopedic tissue engineering. Let’s dive in.

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The Arnie I Knew

I began researching how to use MSCs to treat common orthopedic and spine problems in 2004. It wasn’t long before I came across multiple papers that Arnie had authored. So I have to say that when I met him at a 2011 conference, I was a bit starstruck. However, I quickly learned two key things about “Arnold” Caplan. First, he was Arnie who was just a regular guy. He was funny and had a crazy ability to take complex science and make it understandable for physicians. That led to my second discovery. Arnie believed that MSCs should be used clinically as rapidly as was feasible. That was at a time when other bench scientists had declared a “jihad” against any physician who was using these cells to help patients. While some of that was reasonable as abuses abounded, some of that energy was misplaced. Arnie took a different approach. He would lecture at the conferences where these physicians congregated because he knew, unlike many of his research scientist colleagues, that it was ultimately physicians who would make his MSC discovery real for patients.

Who Was Arnie Caplan the Scientist?

Arnie had almost 500 publications to his name. Hence, this will be just a smattering of all of that work.

Arnie received his Ph.D. at Johns Hopkins Medical School in biochemistry studying the chemical processes within mitochondria when Lyndon Johnson was president. He then stayed on as a post-doc to delve into understanding the mitochondria at the cellular level. There he worked out the basis for the mitochondrial “battery” theory as we know it today. He then switched to Brandies University where he focused on muscle and cartilage development in the late 1960s.

By the early 70s, about the time of Watergate, Arnie had made a home at Case Western where he founded the Cellular and Molecular Biology Training Program. Basically, bridging the gap between biochemistry and biology. By the mid-70s, while Gerald Ford was in office, he was studying animal models of how cartilage and muscles formed from the mesoderm (1). By 1976 and America’s Bicentennial, he had published a series of papers that led him to believe that specific cells played a role in the development of all mesodermal tissues like cartilage, bone, and muscle (2-5).

It was a 1977 paper that would eventually turn Arnie into a science rock star. In that paper, he coined the term “mesenchymal stem cells” (MSCs) (6). These were cells that came from the mesoderm, but that could turn into any mesodermal cell type. Through the late 1970s and into the early 80s, about when the US had its Iran hostage crisis, he continued his research into MSCs (7-17). By the late 80s, while Reagan was president, Arnie had moved from how MSCs were involved in embryonic development to a new idea, that they were also involved in tissue repair and maintenance in adults (18-23).

By 1991, Arnie wrote his seminal paper entitled simply “Mesenchymal Stem Cells” and published it in an orthopedic journal, announcing to the world that these cells would be a big deal in the future (24). This is what he wrote:

“The study of these mesenchymal stem cells, whether isolated from embryos or adults, provides the basis for the emergence of a new therapeutic technology of self-cell repair. The isolation, mitotic expansion, and site-directed delivery of autologous stem cells can govern the rapid and specific repair of skeletal tissues.”

Remember that this was 1991, Operation Desert Storm was underway, and most physicians had no idea that cellular therapies were feasible.

Throughout the 90s, when Bush 1 and Clinton were in the White House, Arnie continued to study orthopedic tissue repair (25-41). He found out that MSCs could repair tendons, meniscus, cartilage, and bone. In essence, he became one of the fathers of orthopedic tissue engineering.

In the early 2000s, at the same time that Bush 2 was discussing weapons of mass destruction in Iraq, Arnie published numerous articles and book chapters exploring this idea of orthopedic tissue regeneration with MSCs and exactly how that worked (42-55). In 2006, he published his next seminal paper that again changed the game about how we thought about MSCs (56). Here Arnie introduced the concept that while MSCs could differentiate into the needed tissues during repair, they also acted as general contractors by issuing commands through cytokines that orchestrated other repair cells.

From here and up until his death, Arnie continued to refine the science of MSCs and explore many other uses for these cells including nerve and lung repair (57-61). In 2010 he again shook up the world of MSC research by changing the name of these cells to Medicinal Signaling Cells (62). By 2014, Arnie even commented on what he saw as a too onerous FDA approval pathway for MSCs and similar products (63).

Arnie the Entrenpeneur

Arnie began a company called Osiris Therapeutics which was founded in 1993 to commercialize MSCs. By 2010 the company had received regulatory approval for its allogeneic MSC-based drug called Prochymal to treat Graft Vs. Host Disease. That drug was later sold to Mesoblast, an Australian company. Osiris also fielded drug candidates for cartilage and bone repair as well as surgical grafts. In 2019, Osiris was acquired for $660 million by Smith and Nephew.

The Big Picture

Arnie will be sorely missed at the myriad of physician regen med conferences he would frequent. However, the bigger picture is that the field has lost the MSC OG. I will personally miss yucking it up with the guy who started it all.

Arnie was able to train an army of scientists who will continue his work, but they have all lost a mentor. However, many of these researchers will continue to push the field he began forward.

Arnie also inspired an army of young physicians to begin using regulatory-compliant versions of MSC therapies in real patients. These responsible physicians will continue to figure out what works and what doesn’t. As he predicted, these doctors are the rubber that meets the road and will continue to figure out how to take his lab discovery into the real world to help people. I know he will be smiling down on all of us with every patient whose life is improved.

Finally, we will all miss Arnie the regular guy who was so approachable and always up for a laugh.

The upshot? This week the field lost a founder, but since Arnie was so prolific and able to touch and inspire so many of us, his legacy will live on in countless scientists and physicians who will continue to take his discovery and use it to help millions!

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References:

(1) AI Caplan and MJ Rosenberg. Interrelationship Between Poly(Adenosine Diphosphoribose) Synthesis, Intracellular NAD Levels, and Muscle or Cartilage Differentiation from Embryonic Chick Limb Mesodermal Cells. Proc Natl Acad Sci 72:1852-1857 (1975).

(2) AI Caplan and MJ Rosenberg. The Control of Chondrogenic and Myogenic Expression in Chick Limb Mesodermal Cells. In: Extracellular Matrix Influences on Gene Expression, Ed. H.C. Slavkin and R. Greulich, Academic Press, New York, pp. 47-55 (1975).

(3) AI Caplan. Biochemical Influences on Organ and Tissue Differentiation. In: 7th Mead Johnson Symposium in Perinatal and Developmental Medicine: Clinical and Biological Aspects of Malformation, Ed. R.S. Bloom, J.C. Sinclair and J.B. Warshaw, pp. 38-53 (1975). 1976

(4) VC Hascall, TR Oegema, M Brown and AI Caplan. Isolation and Characterization of Proteoglycans from Avian Embryonic Limb Bud Chondrocytes Grown In Vitro. J Biol Chem 251:3511-3519 (1976).

(5) Osdoby and AI Caplan. The Possible Differentiation of Osteogenic Elements In Vitro from Chick Limb Mesodermal Cells: I. Morphological Evidence. Dev Biol 52:283-299 (1976).

(6) AI Caplan. Muscle, Cartilage and Bone Development and Differentiation from Chick Limb Mesenchymal Cells. In: Vertebrate Limb and Somite Morphogenesis. Ed. DA Ede, JR Hinchliffe and M Balls, Cambridge University Press, Cambridge, England, pp. 199-213 (1977).

(7) AI Caplan, C Neidergang, H Okazaki and P Mandel. Poly(ADP-ribose) Levels as a Function of Chick Limb Mesenchymal Cell Development as Studied In Vitro and In Vivo. Dev Biol 72:102-109 (1979).

(8) P Osdoby and AI Caplan. Osteogenesis in Cultures of Limb Mesenchymal Cells. Dev Biol 73:84-102 (1979).

(9) LS Lohmander, VC Hascall and AI Caplan. Effects of 4-Methyl Umbelliferyl-ß-D-Xylopyranoside on Chondrogenesis and Proteoglycan Synthesis in Chick Limb Bud Mesenchymal Cell Cultures. J Biol Chem 254:10551-10561 (1979).

(10) P Osdoby and AI Caplan. Characterization of a Bone-Specific Alkaline Phosphatase in Cultures of Chick Limb Mesenchymal Cells. Dev Biol 86:136-146 (1981).

(11) JE Zull, K Youngman and AI Caplan. The Development of Hormonal Responses of Cultured Embryonic Chick Limb Mesenchymal Cells. Dev Biol 86:61-68 (1981).

(12) K von der Mark, P Osdoby and AI Caplan. Effect of 4-Methyl Umbelliferyl-ß-D-Xyloside on Collagen Synthesis in Chick Limb Bud Mesenchymal Cell Cultures. Dev Biol 90:24-30 (1982).

(13) 61. SJ Hunter and AI Caplan. The Control of Cartilage Differentiation. In: Cartilage, Vol. II, Development and Differentiation, Ed. BK Hall, Academic Press, New York, pp. 87-120 (1983).

(14) AI Caplan, GT Syftestad and P Osdoby. The Development of Bone and Cartilage in Tissue Culture. J Clin Ortho Rel Res. 174:243-263 (1983).

(15) DA Carrino, DP Lennon and AI Caplan. Extracellular Matrix and the Maintenance of the Differentiated State: Proteoglycans Synthesized by Replated Chondrocytes and Non-Chondrocytes. Dev Biol 99:132-144 (1983).

(16) GT Syftestad and AI Caplan. A Fraction from Extracts from Demineralized Bone Stimulates the Conversion of Mesenchymal Cells into Chondrocytes. Dev Biol 104:348-356 (1984).

(17) GT Syftestad and AI Caplan. Effects of Osteoinductive Bone Matrix Extracts on the Transition of Mesenchymal Cells into Chondrocytes. Calc Tiss Intl 36:625-627 (1984).

(18) AI Caplan. Bone Development and Repair. BioEssays 6:171-175 (1987).

(19) AI Caplan. Cell and Molecular Strategies for Massive Bone Repair/Regeneration, Japanese Orthopaedic Research Society, Special Lectures at a Glance, Tokyo, Japan, pp. 97-104 (1988).

(20) H Ohgushi, VM Goldberg and AI Caplan. Heterotopic Osteogenesis in Porous Ceramics Induced by Marrow Cells. J Ortho Res 7:568-578 (1989).

(21) H Ohgushi, VM Goldberg and AI Caplan. Repair of Bone Defects with Marrow Cells and Porous Ceramic. Acta Scandia Ortho 60:334-339 (1989).

(22) H Ohgushi, M Okumura, K Masuhara, VM Goldberg, DT Davy and AI Caplan. Calcium Phosphate Block Ceramic with Bone Marrow Cells Improves Repair of Rat Long Bone Defect” and “Osteogenic Potential of Bone Marrow Sustained by Porous Calcium Phosphate Ceramics. In: Handbook of Bioactive Ceramics, Volume II: Calcium Phosphate and Hydroxylapatite Ceramics, Ed. T Yamamuro, LL Hench and J WilsonHerch, CRC Press, Inc., Boca Raton, Florida, (1989).

(23) AI Caplan. Cell Delivery and Tissue Regeneration. J Contr Release 11:157-165 (1989).

(24) AI Caplan. Mesenchymal Stem Cells. J Ortho Res 9:641-650 (1991).

(25) AI Caplan. Regenerating Tissues in Adults. In: Controversies of Total Knee Arthroplasty, Ed. VM Goldberg, Raven Press, New York, pp. 249-252 (1991).

(26) AI Caplan, T Goto, S Wakitani, SJ Pineda, SE Haynesworth and VM Goldberg. Cell-Based Technologies for Cartilage Repair. In: Biology and Biomechanics of the Traumatized Synovial Joint: The Knee as a Model, Edited by GAM Finerman and FR Noyes Publisher: American Academy of Orthopaedic Surgeons, Rosemont, IL, pp. 111-122 (1992).

(27) AI Caplan, DJ Fink, T Goto, AE Linton, RG Young, S Wakitani, VM Goldberg and SE Haynesworth. Mesenchymal Stem Cells and Tissue Repair. In: The Anterior Cruciate Ligament: Current and Future Concepts, Eds. D Jackson, S Arnoczky, S Woo and C Frank, Raven Press, New York, pp. 405-417 (1993).

(28) S Wakitani, T Goto, SJ Pineda, RG Young, JM Mansour, VM Goldberg and AI Caplan. Mesenchymal Cell-Based Repair of Large Full-Thickness Defects of Articular Cartilage and Underlying Bone. J Bone Joint Surg 76:579-592 (1994).

(29) AI Caplan and SP Bruder. Cell and Molecular Engineering of Bone Regeneration. In: Principles of Tissue Engineering, Ed., RP Lanza, WL Chick, and R Langer. RG Landes Co. (Springer, NY) pp. 599-618 (1996).

(30) AI Caplan, M Elyaderani, Y Mochizuki, S Wakitani, and VM Goldberg. The Principles of Cartilage Repair/Regeneration. Clin Orth Rel Res 342:254-269 (1997).

(31) HM Lazarus, MA Thiede, SE Haynesworth, SL Gerson and AI Caplan. Human Bone Marrow-Derived Mesenchymal Progenitor Cells (MPCs) Cannot Be Recovered From Peripheral Blood Progenitor Cell Collections. J Hematotherapy 6:447-455 (1998).

(32) AI Caplan, DJ Fink, SP Bruder, RG Young and DL Butler. The Regeneration of Skeletal Tissues Using Mesenchymal Stem Cells. In: Frontiers in Tissue Engineering Eds. CW Patrick Jr., AG Mikos and LV McIntire, Elsevier Science, New York, Chapter III.7, Pages 471-480 (1998).

(33) B Johnstone, TM Hering, VM Goldberg, JU Yoo, and AI Caplan. In Vitro Chondrogenesis of Bone Marrow-Derived Mesenchymal Progenitor Cells. Exp Cell Res 238:265-272 (1998).

(34) Young RG, Butler DL, Weber W, Caplan AI, Gordon SL, Fink DJ. Use of Mesenchymal Stem Cells in Achilles Tendon Repair. J Orthop Res 16:406-413 (1998).

(35) JU Yoo, TS Barthel, K Nishimura, LA Solchaga, AI Caplan, VM Goldberg, and B Johnstone. The Chondrogenic Potential of Human Bone-Marrow-Derived Mesenchymal Progenitor Cells. J Bone and Joint Surg 80:1745-1757 (1998).

(36) VM Goldberg, LA Solchaga, J Yoo, B Johnstone and AI Caplan. Chondroprogenitor Cell Repair of Full Thickness Defects of Articular Cartilage. J Sports Traumatol 20: 81-89 (1999).

(37) H Awad, DL Butler, P Malaviag, GP Boivin, FNL Smith, B Huibregste, and AI Caplan. Autologous Mesenchymal Stem Cell-Mediated Repair of Tendon. Tissue Eng 5 (3): 267-277 (1999).

(38) CJ Walsh, D Goodman , AI Caplan and VM Goldberg. Meniscus Regeneration in a Rabbit Partial Meniscectomy Model. Tissue Eng 5:327-337. (1999).

(39) VM Goldberg, LA Solchaga, M Lundberg, J Yoo, B Johnstone, B Huibregtse, AI Caplan. Regenerative Cell-based Repair of Osteochondral Defects of Articular Cartilage. Semin Arthrop 10:30-36, (1999).

(40) AI Caplan. Tissue Engineering Strategies for Mesenchymal or Skeletal Tissues. In: Tissue Eng for Therapeutic Use 4: Proceedings of the 4th Intl Symp on Tiss Eng, Eds. Y Ikada and Y Shimizu Elsevier Science, BV: Kyoto, Japan, September, 1999, pp 67-72.

(41) AI Caplan and SP Bruder. Mesenchymal Stem Cells: Building Blocks for Molecular Medicine in the 21st Century. Trends in Molecular Medicine 6:259-264 (2001).

(42) LA Solchaga, VM Goldberg, and AI Caplan. Cartilage Regeneration Using Principles of Tissue Engineering. Clin Orthop Suppl 391:S161-S170 (2001).

(43) AI Caplan. In Vivo Remodeling” In: Reparative Medicine: Growing Tissues and Organs, Ann. NY Acad Sci, 961:307-309 (2002).

(44) A Naumann, JE Dennis, R Staudenmaier, N Rotter, J Aigner, B Ziegelaar, T Happ, G Rasp, AI Caplan, Mesenchymal Stem Cells – A New Pathway for Tissue Engineering in Reconstructive Surgery. Laryngo Rhino Otol 81:521-527 (2003).

(45) LA Solchaga, VM Goldberg and AI Caplan. Cartilage Repair with Bone Marrow in a Hyaluronan-Based Scaffold. In: Hyaluronan eds. JF Kennedy, GO Phillips, PA Williams and VC Hascall. Woodhead Pub. Limited, Cambridge, England, Vol. 2, pp. 63-66 (2003).

(46) JE Dennis, LA Solchaga, AI Caplan, Book Chapter: Chapter 10. Human Mesenchymal Stem Cells for Cartilage Repair. In: Mesenchymal stem cells: biology and potential clinical uses, pp 157-168. Ed by S Grisolía, MD Miñana and EB Bendala-Tufanisco. Madrid, Spain, Ministerio De Sanidad Y Consumo, 2003.

(47) LA Solchaga and AI Caplan. Potential Use of a Novel Hyaluronan-Based Delivery Vehicle in Bone Regeneration. In: Hyaluronan eds. JF Kennedy, GO Phillips, PA Williams and VC Hascall. Woodhead Pub. Limited, Cambridge, England, Vol. 2, pp. 67-70 (2003).

(48) JE Dennis, N Cohen, VM Goldberg, AI Caplan. Targeted Delivery of Progenitor Cells for Cartilage Repair. J Orthop Res 22:735-741, 2004.

(49) VM Goldberg and AI Caplan. Principles of Tissue Engineering and Regeneration of Skeletal Tissues, In: Orthopedic Tissue Engineering Basic Science and Practice. Eds. VM Goldberg, AI Caplan, Marcel Dekker, Inc. New York, NY, Chapter 1, pp. 1-9, 2004.

(50) LA Solchaga, JF Welter, DP Lennon, AI Caplan. Generation of Pluripotent Stem Cells and Their Differentiation to the Chondrocytic Phenotype, In: Cartilage and Osteoarthritis Volume 1 Cellular and Molecular Tools, M Sabatini, P Pastoureau, FD Ceuninck eds., The Humana Press, Totowa, NJ, pp. 53-67, 2004.

(51) AI Caplan. Mesenchymal Stem Cells, In: Handbook of Stem Cells, Vol 2, Academic Press, pp. 299-308, 2004.

(52) LA Solchaga, K Penick, JD Porter, VM Goldberg, AI Caplan, JF Welter. FGF-2 Enhances the Mitotic and Chondrogenic Potentials of Human Adult Bone Marrow-Derived Mesenchymal Stem Cells. J Cell Physiol, J Cell. Physiol 203:398-409, 2005.

(53) D Dean, MS Wolfe, Y Ahmad, A Totonchi, JE-K Chen, JP Fisher, MN Cooke, CM Rimnac, DP Lennon, AI Caplan, NS Topham, AG Mikos. The Effect of TGF-β2 on Marrow-infused-foam Poly(Propylene Fumarate) Tissue Engineered Constructs for the Repair of a Critical Size Cranial Defect in the Rabbit. Tiss Eng 11:923-939, 2005.

(54) AI Caplan. Mesenchymal Stem Cell: Cell-Based Reconstructive Therapy in Orthopaedics. Tiss Eng 11:1198-1211, 2005.

(55) AI Caplan. Mesenchymal Stem Cells, In: Essentials of Stem Cell Biology, R Lanza, J Gearhart, B Hogan, D Melton, R Pedersen, ED Thomas, J Thomason, M West eds., Elsevier Academic Press, Ch. 27, pp. 205-210, 2005.

(56) AI Caplan and JE Dennis. Mesenchymal Stem Cells as Trophic Mediators. J Cell Biochem, 98:1076-1084, 2006.

(57) AI Caplan. Why are MSCs therapeutic? New data: new insight. J Pathol, 217:318-324, 2009.

(58) J Wagner, T Kean, R Young, JE Dennis and AI Caplan. Optimizing mesenchymal stem cell-based therapeutics. Curr Opin Biotechnol, 20:531-536, 2009.

(59) AI Caplan. Mesenchymal stem cells: The past, the present, the future. Cartilage 1(1)6-9, 2010.

(60) TL Bonfield and AI Caplan. Adult mesenchymal stem cells: An innovative therapeutic for lung diseases. Discovery Medicine, 9(47):337-345, 2010. PMID:20423678.

(61) RH Miller, L Bai, DP Lennon, AI Caplan. The potential of mesenchymal stem cells for neural repair. Discovery Medicine, 9(46):236-242, 2010. PMID:20350491

(62) AI Caplan. What’s in a name? Tiss Eng, Part A, 16(8):2415-2417, 2010. PMID: 20412005.

(63) AI Caplan, MD West. Progressive approval: A proposal for a new regulatory pathway for regenerative medicine. Stem Cells Trans Med 3(5):560-563, 2014. PMCID: PMC4006487.