Is Adipocyte Differentiation the Default Lineage for Mesenchymal Stem/Progenitor Cells after Loss of Mechanical Loading? A Perspective from Space Flight and Model Systems


Mesenchymal stem/progenitor cells (MSC/MPC) are found in many tissues and fluids including bone marrow, adipose tissues, muscle, synovial membranes, synovial fluid, and blood. Such cells from different sources can proliferate and differentiate into different lineages (e.g. osteogenic, chondrogenic and adipogenic) after suitable stimulation. However, details regarding the regulation of MSC/MPC proliferation and differentiation status are still unclear and it is likely that regulation involves both biological and mechanical influences in the different environments. It has been noted that in humans and preclinical animal models that exposure to microgravity/space flight or prolonged bed rest (a surrogate for microgravity) can lead to infiltration of skeletal muscle and bone marrow with fat. Similarly, in preclinical models treated with multiple intramuscular injections of Botulinum Toxin A to induce muscle weakness and atrophy, there is also an infiltration of the muscle with fat. The origins and basis for these fat deposits are largely unknown, but there is a possibility that the altered mechanical and biological environments lead to dysregulation of MSC/MPC and progression to preferential differentiation towards the adipocyte lineage. Furthermore, loss of MSC regulatory control by either mechanical and/or biological factors may also contribute to their involvement in obesity development and progression. Thus, the utility of using MSC/MPC from some sources for tissue engineering purposes may be compromised and further research regarding optimal loading for tissue engineering purposes is likely warranted.

Share and Cite:

Hart, D. (2014) Is Adipocyte Differentiation the Default Lineage for Mesenchymal Stem/Progenitor Cells after Loss of Mechanical Loading? A Perspective from Space Flight and Model Systems. Journal of Biomedical Science and Engineering, 7, 799-808. doi: 10.4236/jbise.2014.710079.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Hart, D.A. (2014) Perspectives on Endogenous and Exogenous Tissue Engineering Following Injury to Tissues of the Knee. Journal of Biomedical Science and Engineering, 7, 58-66.
[2] Hart, D.A. (2014) Why Mesenchymal Stem Cell/Progenitor Cell Heterogeneity in Specific Environments? —Implications for Tissue Engineering Following Injury or Degeneration of Connective Tissues. Journal of Biomedical Science and Engineering, 7, 526-532.
[3] Ando, W., Kutcher, J.J., Krawetz, R., Sen, A., Nakamura, N., Frank, C.B. and Hart, D.A. (2014) Clonal Analysis of Synovial Fluid Stem Cells to Characterize and Identify Mesenchymal Stromal Cell/Mesenchymal Progenitor Cell Phenotypes in a Porcine Model: A Cell Source with Enhance Commitment to the Chondrogenic Lineage. Cytotherapy, Feb 12, E-Pub ahead of print.
[4] Borlongan, C.V., Glover, L.E., Tajiri, N., Kaneko, Y. and Freeman, T.B. (2011) The Great Migration of Bone Marrow-Derived Stem Cells towards the Ischemic Brain: Therapeutic Implications for Stroke and Other Neurological Disorders. Progress in Neurobiology, 95, 213-228.
[5] Wu, Y. and Zhao, R.C. (2012) The Role of Chemokines in Mesenchymal Stem Cell Homing to the Myocardium. Stem Cell Reviews, 8, 243-250.
[6] Li, L. and Jiang, J. (2011) Regulatory Factors of Mesenchymal Stem Cell Migration into Injured Tissues and Their Signal Transduction Mechanisms. Frontiers in Medicine, 5, 33-39.
[7] Ando, W., Heard, B., Nakamura, N., Frank, C.B. and Hart, D.A. (2012) Ovine Synovial Membrane-Derived Mescenchymal Progenitor Cells Retain the Phenotype of the Original Tissue That Was Exposed to in Vivo Inflammation: Evidence for a Suppressed Chondrogenic Differentiation Potential of the Cells. Inflammation Research, 61, 599-608.
[8] Gimble, J.M., Bunnell, B.A. and Guilak, F. (2012) Human Adipose-Derived Cells: An Update on the Transition to Clinical Translation. Regenerative Medicine, 7, 225-235.
[9] Fehrer, C. and Lepperdinger, G. (2005) Mesenchymal Stem Cell Aging. Experimental Gerontology, 40, 926-930.
[10] Batsali, A.K., Kastrinaki, M.C., Papadaki, H.A. and Pontikoglou, C. (2013) Mesenchymal Stem Cells Derived from Wharton’s Jelly of the Umbilical Cord: Biological Properties and Emerging Clinical Applications. Current Stem Cell Research and Therapeutics, 8, 144-155.
[11] Deasy, B.M., Schugar, R.C. and Huard, J. (2008) Sex Differences in Muscle-Derived Stem Cells and Skeletal Muscle. Critical Reviews in Eukaryotic Gene Expression, 18, 173-188.
[12] Herrmann, J.L., Abarbanell, A.M., Weil, B.R., Manukyan, M.C., et al. (2010) Gender Dimorphisms in Progenitor and Stem Cell Function in Cardiovascular Disease. Journal of Cardiovascular and Translational Research, 3, 103-113.
[13] Kim, J.H., Jung, Y., Kim, B.S. and Kim, S.H. (2013) Stem Cell Recruitment and Angiogenesis of Neuropeptide Substance P Coupled with Self-Assembly Peptide Nanofiber in a Mouse Hind Limb Ischemia Model. Biomaterials, 34, 1657-1668.
[14] Horie, M., Sekiya, I., Muneta, T., Ichinose, S., et al. (2009) Intra-Articular Injected Synovial Stem Cells Differentiate into Meniscal Cells Directly and Promote Meniscal Regeneration without Mobilization to Distant Organs in Rat Massive Meniscal Defects. Stem Cells, 27, 878-887.
[15] Gharaibeh, B., Lavasani, M., Cummins, J.H. and Huard, J. (2011) Terminal Differentiation Is Not a Major Determinant for the Success of Stem Cell Therapy-Cross-Talk between Muscle-Derived Stem Cells and Host Cells. Stem Cell Research and Therapeutics, 2, 31.
[16] Harris, Q., Seto, J., O’Brien, K., Lee, P.S., Kondo, C., Heard, B.J., Hart, D.A. and Krawetz, R.J. (2013) Monocyte Chemotactic Protein-1 Inhibits Chondrogenesis of Synovial Mesenchymal Progenitor Cells: An in Vitro Study. Stem Cells, 31, 2253-2265.
[17] Krawetz, R., Wu, Y.E., Martin, L., Rattner, J.B., Matyas, J.R. and Hart, D.A. (2012) Correction: Synovial Fluid Progenitors Expressing CD90+ from Normal but Not Osteoarthritis Joints Undergo Chondrogenic Differentiation without Micro-Mass Culture. PLoS ONE, 7, Article ID: e43616.
[18] Hart, D.A., Frank, C.B. and Bray, R.C. (1995) Inflammatory Processes in Repetitive Motion and Over-Use Syndromes: Potential Role of Neurogenic Mechanisms in Tendons and Ligaments. In: Gordon, S.L., Blair, S.J. and Fine, L.J., Eds., Repetitive Motion Disorders of the Upper Extremity, AAOS, Park Ridge, Illinois, 247-262.
[19] Hart, D.A., Frank, C.B., Kydd, A., Ivie, T., et al. (2005) Neurogenic, Mast Cell and Gender Variables in Tendon Biology: Potential Role in Chronic Tendinopathy. In: Muffulli, N., Renstrom, P. and Leadbetter, W., Eds., Tendinopathy: Basic Science and Clinical Management, Springer-Verlag, London, 40-48.
[20] Monument, M.J., Hart, D.A., Salo, P.T., Befus, A.D. and Hildebrand, K.A. (2013) Posttraumatic Elbow Contractures: Targeting Neuroinflammatory Fibrogenic Mechanisms. Journal of Orthopaedic Science, 18, 869-877.
[21] Monument, M.J., Hart, D.A., Salo, P.T., Befus, A.D. and Hildebrand, K.A. (2014) Neuro-Inflammatory Mechanisms of Connective Tissue Fibrosis: Targeting Neurogenic and Mast Cell Contributions. Advances in Wound Care, in press.
[22] Hess, R., Douglas, T., Myers, K.A., Rentsch, C., Worch, H., Shrive, N.G., Hart, D.A. and Scharnweber, D. (2010) Hydrostatic Pressure (HP) Stimulation of Human Mesenchymal Stem Cells (hMSC) Seeded on Collagen-Based Artificial Extracellular Matrices. Journal of Biomechanical Engineering, 132, Article ID: 021001.
[23] Cao, B. and Huard, J. (2004) Muscle-Derived Stem Cells. Cell Cycle, 3, 104-107.
[24] Usas, A., Maciulaitis, J., Maciulaitis, R., Jakuboniene, N., Milašius, A. and Huard, J. (2011) Skeletal Muscle-Derived Stem Cells: Implications for Cell-Mediated Therapies. Medicina (Kaunas), 47, 469-479.
[25] Chen, C.W., Corselli, M., Peault, B. and Huard, J. (2012) Human Blood-Vessel-Derived Stem Cells for Tissue Repair and Regeneration. Journal of Biomedicine and Biotechnology, 2012, Article ID: 597439.
[26] Longino, D., Butterfield, T.A. and Herzog, W. (2005) Frequency and Length-Dependent Effects of Botulinum Toxin-Induced Muscle Weakness. Journal of Biomechanics, 38, 609-613.
[27] Longino, D., Frank, C., Leonard, T.R., Vaz, M.A. and Herzog, W. (2005) Proposed Model of Botulinum Toxin-Induced Muscle Weakness in the Rabbit. Journal of Orthopaedic Research, 23, 1411-1418.
[28] Leumann, A., Longino, D., Fortuna, R., Leonard, T., Vaz, M., Hart, D.A. and Herzog, W. (2012) Altered Cell Metabolism in Tissues of the Knee Joint in a Rabbit Model of Botulinum Toxin A-Induced Quadriceps Muscle Weakness. Scandinavian Journal of Medicine & Science in Sports, 22, 776-782.
[29] Herbison, G.J. and Talbot, J.M. (1985) Muscle Atrophy during Space Flight: Research Needs and Opportunities. Physiologist, 28, 520-527.
[30] Hawkey, A. (2003) The Physical Price of a Ticket into Space. Journal of the British Interplanetary Society, 56, 152-159.
[31] Narici, M.V. and de Boer, M.D. (2011) Disuse of the Musculo-Skeletal System in Space and on Earth. European Journal of Applied Physiology, 111, 403-420.
[32] Smith, S.M., Heer, M.A., Shackelford, L.C., Sibonga, J.D., Ploutz-Snyder, L. and Zwart, S.R. (2012) Benefits for Bone from Resistance Exercise and Nutrition in Long-Duration Spaceflight: Evidence from Biochemistry and Densitometry. Journal of Bone and Mineral Research, 27, 1896-1906.
[33] Heer, M., Kamps, N., Biener, C., Korr, C., et al. (1999) Calcium Metabolism in Microgravity. European Journal of Medical Research, 4, 357-360.
[34] Rittweger, J., Gunga, H.C., Felsenberg, D. and Kirsch, K.A. (1999) Muscle and Bone-Aging and Space. Journal of Gravitational Physiology, 6, P133-P136.
[35] Biolo, G., Heer, M., Narici, M. and Strollo, F. (2003) Microgravity as a Model of Aging. Current Opinion in Clinical Nutrition and Metabolic Care, 6, 31-40.
[36] Vernikos, J. and Schneider, V.S. (2010) Space, Gravity and the Physiology of Aging: Parallel or Convergent Disciplines? A Mini-Review. Gerontology, 56, 157-166.
[37] Stein, T.P. and Wade, C.E. (2005) Metabolic Consequences of Muscle Disuse Atrophy. Journal of Nutrition, 135, 1824S-1828S.
[38] LeBlanc, A.D., Spector, E.R., Evans, H.J. and Sibonga, J.D. (2007) Skeletal Responses to Space Flight and the Bed Rest Analog: A Review. Journal of Musculoskeletal and Neuronal Interactions, 7, 33-47.
[39] Jost, P.D. (2008) Simulating Human Space Physiology with Bed Rest. Hippokratia, 12, 37-40.
[40] Kos, O., Hughson, R.L., Hart, D.A., Clement, G., Frings-Meuthen, P., Linnarsson, D., et al. (2014) Elevated Serum Soluble CD200 and CD200R as Surrogate Markers of Bone Loss under Bed Rest Conditions. Bone, 60, 33-40.
[41] Trudel, G., Payne, M., Madler, B., Ramachandran, N., Lecompte, M., Wade, C., Biolo, G., Blanc, S., Hughson, R., Bear, L. and Uhthoff, H.K. (2009) Bone Marrow Fat Accumulation after 60 Days of Bed Rest Persisted 1 Year Activities Were Resumed along with Hemopoietic Stimulation: The Women International Space Simulation of Exploration Study. Journal of Applied Physiology (1985), 107, 540-548.
[42] Trudel, G., Coletta, E., Cameron, I., Belavy, D.L., Lecompte, M., Armbrecht, G., Felsenberg, D. and Uhthoff, H.K. (2012) Resistive Exercises, with or without Whole Body Vibration, Prevent Vertebral Marrow Fat Accumulation during 60 Days of Head-Down Tilt Bed Rest in Men. Journal of Applied Physiology (1985), 112, 1824-1831.
[43] Wronski, T.J. and Morey, E.R. (1982) Skeletal Abnormalities in Rats Induced by Simulated Weightlessness. Metabolic Bone Disease and Related Research, 4, 69-75.
[44] Myers, V.E., Zayzafoon, M., Douglas, J.T. and McDonald, J.M. (2005) RhoA and Cytoskeletal Disruption Mediate Reduced Osteoblastogenesis and Enhanced Adipogenesis of Human Mesenchymal Stem Cells in Modeled Microgravity. Journal of Bone and Mineral Research, 20, 1858-1866.
[45] Luu, Y.K., Capilla, E., Rosen, C.J., Gilsanz, V., Pessin, J.E., Judex, S. and Rubin, C.T. (2009) Mechanical Stimulation of Mesenchymal Stem Cell Proliferation and Differentiation Promotes Osteogenesis While Preventing Dietary-Induced Obesity. Journal of Bone and Mineral Research, 24, 50-61.
[46] Luu, Y.K., Pessin, J.E., Judex, S., Rubin, J. and Rubin, C.T. (2009) Mechanical Signals as a Non-Invasive Means to Influence Mesenchymal Stem Cell Fate, Promoting Bone and Suppressing the Fat Phenotype. Bonekey Osteovision, 6, 132-149.
[47] Gutin, B. (2013) How Can We Help People to Develop Lean and Healthy Bodies? A New Perspective. Research Quarterly in Exercise and Sport, 84, 1-5.
[48] Faustini, M., Bucco, M., Chiapanidas, T., Lucconi, G., Marazzi, M., Tosca, M.C., et al. (2010) Nonexpanded Mesenchymal Stem Cells for Regenerative Medicine: Yield in Stromal Vascular Fraction from Adipose Tissues. Tissue Engineering Part C: Methods, 16, 1515-1521.
[49] Wickham, M.Q., Erickson, G.R., Gimble, J.M., Vail, T.P. and Guilak, F. (2003) Multipotent Stomal Cells Derived from the Infrapatellar Fat Pad of the Knee. Clinical Orthopedics and Related Research, 412, 196-212.
[50] Orbay, H., Tobita, M. and Mizuno, H. (2012) Mesenchymal Stem Cells Isolated from Adipose and Other Tissues: Basic Biological Properties and Clinical Applications. Stem Cells International, 2012, Article ID: 461718.
[51] Guilak, F., Awad, H.A., Fermor, B., Leddy, H.A. and Gimble, J.M. (2004) Adipose-Derived Adult Stem Cells for Cartilage Tissue Engineering. Biorheology, 41, 389-399.
[52] Wu, C.L., Diekman, B.O., Jain, D. and Guilak, F. (2013) Diet-Induced Obesity Alters the Differentiation Potential of Stem Cells Isolated from Bone Marrow, Adipose Tissue and Infrapatellar Fat Pad: The Effects of Free Fatty Acids. International Journal of Obesity (London), 37, 1079-1087.
[53] Hassan, M., Latif, N. and Yacoub, M. (2012) Adipose Tissue: Friend or Foe? Nature Reviews Cardiology, 9, 689-702.
[54] Fietta, P. and Delsante, G. (2013) Focus on Adipokines. Theoretical Biology Forum, 106, 103-129.
[55] Purkayastha, S. and Cai, D.S. (2013) Neuroinflammatory Basis of Metabolic Syndrome. Molecular Metabolism, 2, 356-363.
[56] Purkayastha, S. and Cai, D.S. (2013) Disruption of Neurongenesis by Hypothatlamic Inflammation in Obesity or Aging. Reviews in Endocrine and Metabolic Disorders, 14, 351-356.
[57] Jialal, I., Kaur, H. and Devaraj, S. (2014) Toll-Like Receptor Status in Obesity and Metabolic Syndrome: A Translational Perspective. Journal of Clinical Endocrinology and Metabolism, 99, 39-48.
[58] Kim, Y.J., Hwang, S.H., Cho, H.H., Shin, K.K., Bae, Y.C. and Jung, J.S. (2012) MicroRNA 21 Regulates the Proliferation of Human Adipose Tissue-Derived Mesenchymal Stem Cells and High-Fat Diet-Induced Obesity Alters micro-RNA 21 Expression in White Adipose Tissues. Journal of Cellular Physiology, 227, 183-193.
[59] Solbak, N.M., Heard, B.J., Achari, Y., Chung, M., Shrive, N.G., Frank, C.B. and Hart, D.A. (2014) Persistant Molecular and Histologic Changes in the Infrapatellar Fat Pad Following Idealized Anterior Cruciate Ligament Surgery May Compromise the Long Term Integrity of the Ovine Knee. Manuscript Submitted (20 April, 2014).
[60] Estes, B.T., Diekman, B.O. and Guilak, F. (2008) Monolayer Cell Expansion Conditions Affect the Chondrogenic Potential of Adipose-Derived Stem Cells. Biotechnology and Bioengineering, 99, 986-995.
[61] Kang, T., Lu, W., Xu, W., Anderson, L., Bacanamwo, M., Thompson, W., Chen, Y.E. and Liu, D. (2013) MicroRNA-27 (miR-27) Targets Prohibitin and Impairs Adipocyte Differentiation and Mitochondrial Function in Human Adipose-Derived Stem Cells. Journal of Biological Chemistry, 288, 34394-34402.
[62] Oger, F., Gheeraet, C., Mogilenko, D., Benomar, Y., Molendi-Coste, O., Bouchaert, E., et al. (2014) Cell-Specific Dysregulation of microRNA Expression in Obese White Adipose Tissue. The Journal of Clinical Endocrinology & Metabolism, 23, Article ID: jc20134259.
[63] Grunberg, J.R., Hammarstedt, A., Hedjazifar, S. and Smith, U. (2014) The Novel Secreted Adipokine WNT1-Inducible Signaling Pathway Protein 2 (WISP2) Is a Mesenchymal Cell Activator of Canonical WNT. Journal of Biological Chemistry, 289, 6899-6907.
[64] Lee, Y.H., Mottillo, E.P. and Granneman, J.G. (2014) Adipose Tissue Plasticity from WAT to BAT and in between. Biochimica et Biophysica Acta, 1842, 358-369.
[65] Li, J.X., Tang, Y.Z., Purkayastha, S., Yan, J.Q. and Cai, D.S. (2014) Control of Obesity and Glucose Intolerance via Building Neural Stem Cells in the Hypothalamus. Molecular Metabolism, 3, 313-324.
[66] Cai, D.S. (2013) Neuroinflammation and Neurodegeneration in Overnutrition-Induced Diseases. Trends in Endocrinology and Metabolism, 24, 40-47.
[67] Billion, N., Monteiro, M.C. and Dani, C. (2008) Developmental Origin of Adipocytes: New Insights into a Pending Question. Biology of the Cell, 100, 563-575.
[68] McGregor, R.A. and Choi, M.S. (2011) MicroRNAs in the Regulation of Adipogenesis and Obesity. Current Molecular Medicine, 11, 304-316.
[69] Guo, Y.X., Mo, D.L., Zhang, Y., Cong, P.Q., Xiao, S.Q., He, Z.Y., Liu, X.H. and Chen, Y.S. (2012) MicroRNAome Comparison between Intramuscular and Subcutaneous Vascular Stem Cell Adipogenesis. PLoS ONE, 7, Article ID: e45410.
[70] Krause, G., Zhao, P., Martin, L., Fritzler, M., Benediktsson, H. and Hart, D.A. (1992) LiCl Prolongs Survival and Alters Disease Progression in the NZB/W Model of SLE. Lithium, 3, 61-67.
[71] Hart, D.A., Done, S.J., Benediktsson, H. and Lenz, S. (1994) Partial Characterization of the Enhanced Survival of Female NZB/W Mice Treated with Lithium Chloride. International Journal of Immunopharmacology, 16, 825-833.
[72] Hart, D.A. and Lenz, S.P. (1997) Multiple Daily Injections of NZB/W Mice with LiCl Leads to the Long-Term Survival of a High Percentage (80%) of the Animals. Journal of Trace and Microprobe Techniques, 15, 219-227.
[73] Satija, N.K., Sharma, D., Afrin, F., Tripathi, R.P. and Gangenahalli, G. (2013) High Throughput Transcriptome Profiling of Lithium Stimulated Human Mesenchymal Stem Cells Reveals Priming towards Osteoblastic Lineage. PLoS ONE, 8, Article ID: e55769.
[74] Brunt, K.R., Zhang, Y., Mihic, A., Li, M., Li, S.H., et al. (2012) Role of WNT/Beta-Catenin Signaling in Rejuvenating Myogenic Differentiation of Aged Mesenchymal Stem Cells from Cardiac Patients. American Journal of Pathology, 181, 2067-2078.
[75] Payne, M.W., Uhthoff, H.K. and Trudel, G. (2007) Anemia of Immobility: Caused by Adipocyte Accumulation in the Bone Marrow. Medical Hypotheses, 69, 778-786.
[76] Laharrague, P. and Casteilla, L. (2010) The Emergence of Adipocytes. Endocrine Development, 19, 21-30.
[77] Maijka, S.M., Barak, Y. and Klemm, D.J. (2011) Concise Review: Adipocyte Origins: Weighing the Possibilities. Stem Cells, 29, 1034-1040.
[78] Cignarelli, A., Perrini, S., Ficarella, R., Peschechera, A., Nigroa, P. and Giorgino, F. (2012) Human Adipose Tissue Stem Cells: Relevance in the Pathophysiology of Obesity and Metabolic Diseases and Therapeutic Applications. Expert Reviews in Molecular Medicine, 14, e19.
[79] Hwang, J.H., Moon, S.A., Lee, C.H., Byun, M.R., et al. (2012) Idesolide Inhibits the Adipogenic Differentiation of Mesenchymal Cells through the Suppression of Nitric Oxide Production. European Journal of Pharmacology, 685, 218-223.
[80] Bourin, P., Bunnell, B.A., Casteilla, L., Dominici, M., Katz, A.J., March, K.L., Redl, H., Rubin, J.P., Yoshimura, K. and Gimble, J.M. (2013) Stromal Cells from the Adipose Tissue-Derived Stromal Vascular Fraction and Culture Expanded Adipose Tissue-Derived Stromal/Stem Cells: A Joint Statement of the International Federation for Adipose Therapeutics and Science (IFATS and the International Society for Cellular Therapy (ISCT). Cytotherapy, 15, 641-648.

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.