Mesenchymal Stem Cells

In the summer of 1964, I took a graduate pathology course for non-MDs given by Professor Guido Mino at Harvard Medical School. Dr Jerry Gross gave a 2-hour lecture in that course which went from the chemistry and structure of collagen up through the collagenase-mediated destruction of collagen during tadpole tail resorption and metamorphosis. This lecture changed my life forever and set the tone of my thinking and research by demonstrating the continuum of molecules through the control of biological phenomena as seen through the eyes of a biochemist and developmental biologist. In 1967, I started a postdoctoral fellowship with Nathan O. Kaplan, PhD, at Brandeis University where I met and joined the lab of Edgar Zwilling, PhD. Professor Zwilling was a renowned embryologist and developmental biologist1,2 who taught me about these subjects as I started studying the differentiation capacity of undifferentiated embryonic chick limb mesodermal cells in culture.3 These cells were mesenchymal stem cells (MSCs) that have the capabilities to differentiate in vitro into a number of mesodermal phenotypes by controlling the initial seeding density in culture and the medium additives and conditions.4-6 Thus, I was able to study the molecular control of embryonic chick limb cell differentiation and limb development7 in ways complementary to those described by Dr Gross 5 years earlier. This was the start of my MSC journey and experimental exploits.

[1]  Luis Rodriguez-Menocal,et al.  Stimulation of Skin and Wound Fibroblast Migration by Mesenchymal Stem Cells Derived from Normal Donors and Chronic Wound Patients , 2012, Stem cells translational medicine.

[2]  Arnold I Caplan,et al.  The MSC: an injury drugstore. , 2011, Cell stem cell.

[3]  A. J. Putnam,et al.  Effects of extracellular matrix density and mesenchymal stem cells on neovascularization in vivo. , 2011, Tissue engineering. Part A.

[4]  D. Metcalfe,et al.  Bone marrow stromal cells inhibit mast cell function via a COX2‐dependent mechanism , 2011, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[5]  Zhenxing Si,et al.  Locally Administered Adipose-Derived Stem Cells Accelerate Wound Healing through Differentiation and Vasculogenesis , 2011, Cell transplantation.

[6]  A. Caplan,et al.  Human mesenchymal stem cells suppress chronic airway inflammation in the murine ovalbumin asthma model. , 2010, American journal of physiology. Lung cellular and molecular physiology.

[7]  N. Gibran,et al.  Mesenchymal stem cells: paracrine signaling and differentiation during cutaneous wound repair. , 2010, Experimental cell research.

[8]  S MacNeil,et al.  Mesenchymal stem cell-conditioned medium accelerates skin wound healing: an in vitro study of fibroblast and keratinocyte scratch assays. , 2010, Experimental cell research.

[9]  Teruo Okano,et al.  Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice. , 2009, The Journal of clinical investigation.

[10]  M. Pittenger Sleuthing the source of regeneration by MSCs. , 2009, Cell stem cell.

[11]  A. Caplan New era of cell-based orthopedic therapies. , 2009, Tissue engineering. Part B, Reviews.

[12]  A. Caplan Why are MSCs therapeutic? New data: new insight , 2009, The Journal of pathology.

[13]  Arnold I Caplan,et al.  All MSCs are pericytes? , 2008, Cell stem cell.

[14]  S. Badylak,et al.  A perivascular origin for mesenchymal stem cells in multiple human organs. , 2008, Cell stem cell.

[15]  M. Rojas,et al.  Anti-inflammatory effects of mesenchymal stem cells: novel concept for future therapies , 2008, Expert opinion on biological therapy.

[16]  Liwen Chen,et al.  Paracrine Factors of Mesenchymal Stem Cells Recruit Macrophages and Endothelial Lineage Cells and Enhance Wound Healing , 2008, PloS one.

[17]  L. Ortiz,et al.  Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury , 2007, Proceedings of the National Academy of Sciences.

[18]  V. Falanga,et al.  Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds. , 2007, Tissue engineering.

[19]  A. Caplan,et al.  Human Mesenchymal Stem Cells Signals Regulate Neural Stem Cell Fate , 2007, Neurochemical Research.

[20]  Xiaobing Fu,et al.  Adult bone-marrow-derived mesenchymal stem cells contribute to wound healing of skin appendages , 2006, Cell and Tissue Research.

[21]  A. Caplan,et al.  Mesenchymal stem cells as trophic mediators , 2006, Journal of cellular biochemistry.

[22]  Lindolfo da Silva Meirelles,et al.  Mesenchymal stem cells reside in virtually all post-natal organs and tissues , 2006, Journal of Cell Science.

[23]  Xiaobing Fu,et al.  Enhanced wound‐healing quality with bone marrow mesenchymal stem cells autografting after skin injury , 2006, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[24]  F. Guilak,et al.  Potent induction of chondrocytic differentiation of human adipose-derived adult stem cells by bone morphogenetic protein 6. , 2006, Arthritis and rheumatism.

[25]  R. Sidman,et al.  Neural Stem Cells: From In Vivo to In Vitro and Back Again–Practical Aspects , 2003 .

[26]  P. Quesenberry,et al.  Participation of bone marrow derived cells in cutaneous wound healing , 2003, Journal of cellular physiology.

[27]  G. Sukhikh,et al.  Mesenchymal Stem Cells , 2002, Bulletin of Experimental Biology and Medicine.

[28]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

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[30]  S. Gerson,et al.  Phenotypic and functional comparison of cultures of marrow‐derived mesenchymal stem cells (MSCs) and stromal cells , 1998, Journal of cellular physiology.

[31]  D. Butler,et al.  Use of mesenchymal stem cells in a collagen matrix for achilles tendon repair , 1998, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[32]  A I Caplan,et al.  In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells. , 1998, Experimental cell research.

[33]  A I Caplan,et al.  Cytokine expression by human marrow‐derived mesenchymal progenitor cells in vitro: Effects of dexamethasone and IL‐1α , 1996, Journal of cellular physiology.

[34]  A. Caplan,et al.  Myogenic Expression of Mesenchymal Stem Cells within Myotubes of mdx Mice in Vitro and in Vivo. , 1995, Tissue engineering.

[35]  A I Caplan,et al.  Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. , 1995, Bone marrow transplantation.

[36]  J. Sprent,et al.  Lymphocyte activation , 1994, Journal of cellular biochemistry.

[37]  Joseph M. Mansour,et al.  Mesenchymal Cell-Based Repair of Large Full Thickness Defects of Articular Cartilage , 1994 .

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[40]  V. Goldberg,et al.  In vivo osteochondrogenic potential of cultured cells derived from the periosteum. , 1990, Clinical orthopaedics and related research.

[41]  A. Caplan,et al.  Altered cartilage proteoglycans synthesized by chick limb bud chondrocytes cultured in serum-free defined medium. , 1989, Experimental cell research.

[42]  V. Goldberg,et al.  Heterotopic osteogenesis in porous ceramics induced by marrow cells , 1989, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[43]  A. Caplan,et al.  Growth and differentiation of stage 24 limb mesenchyme cells in a serum-free chemically defined medium. , 1989, Experimental cell research.

[44]  J. Connolly,et al.  Development of an osteogenic bone-marrow preparation. , 1989, The Journal of bone and joint surgery. American volume.

[45]  A I Caplan,et al.  Repair of bone defects with marrow cells and porous ceramic. Experiments in rats. , 1989, Acta orthopaedica Scandinavica.

[46]  V. Rosen,et al.  Novel regulators of bone formation: molecular clones and activities. , 1988, Science.

[47]  D. Gazit,et al.  Osteogenesis in in vivo diffusion chamber cultures of human marrow cells. , 1988, Bone and mineral.

[48]  D. Zipori,et al.  Introduction of interleukin-3 gene into stromal cells from the bone marrow alters hemopoietic differentiation but does not modify stem cell renewal. , 1988, Blood.

[49]  M. Owen Marrow stromal stem cells , 1988, Journal of Cell Science.

[50]  A I Caplan,et al.  A water-soluble fraction from adult bone stimulates the differentiation of cartilage in explants of embryonic muscle. , 1988, Differentiation; research in biological diversity.

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[52]  A. Abramovici,et al.  Use of cultured embryonal chick epiphyseal chondrocytes as grafts for defects in chick articular cartilage. , 1987, Clinical orthopaedics and related research.

[53]  A. Friedenstein,et al.  Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers , 1987, Cell and tissue kinetics.

[54]  A. Caplan Bone development and repair , 1987, BioEssays : news and reviews in molecular, cellular and developmental biology.

[55]  A. Caplan The extracellular matrix is instructive. , 1986, BioEssays : news and reviews in molecular, cellular and developmental biology.

[56]  E B Hunziker,et al.  Stereology for anisotropic cells: Application to growth cartilage * , 1986, Journal of microscopy.

[57]  R. Tuan,et al.  Chondrogenesis of limb bud mesenchyme in vitro: stimulation by cations. , 1986, Developmental biology.

[58]  M. Urist,et al.  Regeneration of an enchondroma defect under the influence of an implant of human bone morphogenetic protein. , 1986, The Journal of hand surgery.

[59]  A. Caplan,et al.  Substrate-bonded hyaluronic acid exhibits a size-dependent stimulation of chondrogenic differentiation of stage 24 limb mesenchymal cells in culture. , 1986, Developmental biology.

[60]  A I Caplan,et al.  Hyaluronic acid bonded to cell-culture surfaces stimulates chondrogenesis in stage 24 limb mesenchyme cell cultures. , 1986, Developmental biology.

[61]  A. Caplan,et al.  The in vitro chondrogenic response of limb-bud mesenchyme to a water-soluble fraction prepared from demineralized bone matrix. , 1985, Differentiation; research in biological diversity.

[62]  A. Caplan,et al.  Isolation and characterization of osteogenic cells derived from first bone of the embryonic tibia. , 1985, Developmental biology.

[63]  D. Rosen,et al.  Purification and characterization of two cartilage-inducing factors from bovine demineralized bone. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[64]  T. Schmid,et al.  Developmental acquisition of type X collagen in the embryonic chick tibiotarsus. , 1985, Developmental biology.

[65]  R. Salter,et al.  The induction of neochondrogenesis in free intra-articular periosteal autografts under the influence of continuous passive motion. An experimental investigation in the rabbit. , 1984, The Journal of bone and joint surgery. American volume.

[66]  A. Caplan,et al.  An osteo-inductive bone matrix extract stimulates thein vitro conversion of mesenchyme into chondrocytes , 1984, Calcified Tissue International.

[67]  A. Caplan,et al.  A fraction from extracts of demineralized adult bone stimulates the conversion of mesenchymal cells into chondrocytes. , 1984, Developmental biology.

[68]  C. R. Howlett,et al.  Ultrastructure of bone and cartilage formed in vivo in diffusion chambers. , 1984, Clinical orthopaedics and related research.

[69]  B. Swalla,et al.  Inhibition of limb chondrogenesis by fibronectin. , 1984, Differentiation; research in biological diversity.

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[73]  M. Urist,et al.  Bone cell differentiation and growth factors. , 1983, Science.

[74]  A. Caplan,et al.  Isolated osteoclasts and their presumed progenitor cells, the monocyte, in culture. , 1982, The Journal of experimental zoology.

[75]  T. Schmid,et al.  Metabolism of low molecular weight collagen by chondrocytes obtained from histologically distinct zones of the chick embryo tibiotarsus. , 1982, The Journal of biological chemistry.

[76]  A. Caplan,et al.  Effect of 4-methylumbelliferyl-beta-d-xyloside on collagen synthesis in chick limb bud mesenchymal cell cultures. , 1982, Developmental biology.

[77]  A. Reddi,et al.  Dissociative extraction and reconstitution of extracellular matrix components involved in local bone differentiation. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[78]  M. Solursh,et al.  In vitro histogenic capacities of limb mesenchyme from various stage mouse embryos. , 1981, Developmental biology.

[79]  A. Caplan,et al.  First bone formation in the developing chick limb. , 1981, Developmental biology.

[80]  A. Caplan,et al.  The development of hormonal responses of cultured embryonic chick limb mesenchymal cells. , 1981, Developmental biology.

[81]  A. Caplan,et al.  Characterization of a bone-specific alkaline phosphatase in chick limb mesenchymal cell cultures. , 1981, Developmental biology.

[82]  R. Reiter,et al.  Stage- and position-related changes in chondrogenic response of chick embryonic wing mesenchyme to treatment with dibutyryl cyclic AMP. , 1981, Developmental biology.

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[88]  E. Thonar,et al.  Age-related changes in proteoglycan structure. , 1979, Archives of biochemistry and biophysics.

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[90]  A. Caplan,et al.  Development of parathyroid hormone- and calcitonin-activated adenylate cyclases in embryonic chicken limb and in cultured cells from embryonic chicken limb. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[91]  A. Caplan,et al.  Irreversible gene repression model for control of development. , 1978, Science.

[92]  V. Hascall,et al.  Biosynthesis of proteoglycans by chick limb bud chondrocytes. , 1978, The Journal of biological chemistry.

[93]  D. Heinegård,et al.  Chemical and physical changes in proteoglycans during development of chick limb bud chondrocytes grown in vitro. , 1977, The Journal of biological chemistry.

[94]  L. Lajtha,et al.  Conditions controlling the proliferation of haemopoietic stem cells in vitro , 1977, Journal of cellular physiology.

[95]  T. Oegema,et al.  Isolation and characterization of proteoglycans from chick limb bud chondrocytes grown in vitro. , 1976, The Journal of biological chemistry.

[96]  A. Caplan,et al.  Interrelationship between poly (ADP-Rib) synthesis, intracellular NAD levels, and muscle or cartilage differentiation from mesodermal cells of embryonic chick limb. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[97]  S. Hauschka Clonal analysis of vertebrate myogenesis. 3. Developmental changes in the muscle-colony-forming cells of the human fetal limb. , 1974, Developmental biology.

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[99]  A. Caplan,et al.  The control of muscle and cartilage development in the chick limb: the role of differential vascularization. , 1973, Journal of embryology and experimental morphology.

[100]  A. Caplan The effects of the nicotinamide sensitive teratogen 3-acetylpyridine on chick limb mesodermal cells in culture: biochemical parameters. , 1972, The Journal of experimental zoology.

[101]  A. Caplan Effects of the nicotinamide-sensitive teratogen3-acetylpyridine on chick limb cells in culture. , 1970, Experimental cell research.

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[107]  S. Miller,et al.  Human bone marrow‐derived mesenchymal stem cells induce Th2‐polarized immune response and promote endogenous repair in animal models of multiple sclerosis , 2009, Glia.

[108]  Yasuyuki Fujita,et al.  Mesenchymal Stem Cells Are Recruited into Wounded Skin and Contribute to Wound Repair by Transdifferentiation into Multiple Skin Cell Type , 2008 .

[109]  Catherine M. Verfaillie,et al.  Pluripotency of mesenchymal stem cells derived from adult marrow , 2007, Nature.

[110]  Hajime Ohgushi,et al.  Repair of articular cartilage defects in the patello‐femoral joint with autologous bone marrow mesenchymal cell transplantation: three case reports involving nine defects in five knees , 2007, Journal of tissue engineering and regenerative medicine.

[111]  D. Prockop,et al.  Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. , 2006, Cytotherapy.

[112]  A. Caplan,et al.  A scanning electron microscopic investigation of in vitro osteogenesis , 2006, Calcified Tissue International.

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[115]  S. Gerson,et al.  Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[116]  A. Caplan,et al.  Cell surface antigens on human marrow-derived mesenchymal cells are detected by monoclonal antibodies. , 1992, Bone.

[117]  A I Caplan,et al.  Characterization of cells with osteogenic potential from human marrow. , 1992, Bone.

[118]  T. Shimada,et al.  Three-dimensional architecture of pericytes with special reference to their topographical relationship to microvascular beds. , 1992, Archives of histology and cytology.

[119]  A I Caplan,et al.  The osteogenic potential of culture-expanded rat marrow mesenchymal cells assayed in vivo in calcium phosphate ceramic blocks. , 1991, Clinical orthopaedics and related research.

[120]  A. Caplan,et al.  Comparison of the cartilage proteoglycan core protein synthesized by chondrocytes of different ages. , 1991, Connective tissue research.

[121]  S. Bruder,et al.  Terminal differentiation of osteogenic cells in the embryonic chick tibia is revealed by a monoclonal antibody against osteocytes. , 1990, Bone.

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[124]  S. Bruder,et al.  Discrete stages within the osteogenic lineage are revealed by alterations in the cell surface architecture of embryonic bone cells. , 1989, Connective tissue research.

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[126]  E. Hunziker Growth plate structure and function. , 1988, Pathology and immunopathology research.

[127]  A. Caplan,et al.  Chemotactic response of embryonic limb bud mesenchymal cells and muscle-derived fibroblasts to transforming growth factor-beta. , 1988, Connective tissue research.

[128]  R. Cancedda,et al.  Dimethyl sulfoxide interferes with in vitro differentiation of chick embryo endochondral chondrocytes. , 1988, Developmental biology.

[129]  A. Caplan,et al.  Chemotactic response of mesenchymal cells, fibroblasts and osteoblast-like cells to bone Gla protein. , 1988, Bone.

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[133]  A. Caplan,et al.  Partial isolation and characterization of a chemotactic factor from adult bovine bone for mesenchymal cells. , 1986, Bone.

[134]  A. Caplan,et al.  Morphology of bone development and bone remodeling in embryonic chick limbs. , 1986, Bone.

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[138]  M. Urist,et al.  A quantitative analysis of new bone formation by induction in compositive grafts of bone marrow and bone matrix. , 1980, Clinical Orthopaedics and Related Research.

[139]  A. Friedenstein Precursor cells of mechanocytes. , 1976, International review of cytology.

[140]  A. Caplan Effects of a nicotinamide-sensitive teratogen 6-aminonicotinamide on chick limb cells in culture. , 1972, Experimental cell research.

[141]  E. Zwilling Morphogenetic Phases in Development , 1968 .