透明質酸，為一種人體常見之細胞外基質的成分。實驗室之前研究成果發現，透明質酸介面具有延長間葉幹細胞壽命的功能，並且可減少其老化相關蛋白表現；因此本研究想探討透明質酸如何影響胎盤間葉幹細胞，提供抗老化之功能機制。此研究利用穿透式顯微鏡以及多光子顯微鏡還有原子力顯微鏡發現，將胎盤間葉幹細胞養在透明質酸介面上直至老化的代數，細胞的型態會改變，同時，細胞內部的細胞骨架以及內質網等胞器也會造成變化，並且使細胞維持較不老化的型態。除此之外，利用蛋白質體學研究結果發現，有幾條訊息傳導路線，包含PI3K/AKT、RAS/RAF等路徑，皆是在透明質酸介面上培養的組別表現量較高；同時會造成下游細胞型態改變的p-cofilin以及p-LIMK基因表現量下降。另外，此研究也同時利用磷酸化蛋白質體學來進一步觀察磷酸化蛋白參與哪些訊息傳遞路徑。此研究同時也藉由西方點墨法更多確認相關的蛋白表現量是否與蛋白質體學一致。藉由此研究可以得知，透明質酸可以藉由影響到細胞內訊息傳遞路徑蛋白表現量的變化，進而使細胞能夠產生抗老化之現象。

Hyaluronan, or hyaluronic acid (HA), is one group of extracellular matrix that is abundant in our bodies. In our lab’s previous study, it was reported that HA could prolong the lifespan of MSCs and prevented MSCs from cellular aging with reduced the gene expression of aging genes. As the result, this research wanted to find the mechanism of life-maintained and anti-aging in the placenta-derived mesenchymal stem cells affected by Hyaluronan. By using the transmission electron microscope, atomic force microscope and the multiphoton microscope, the results found that when cultured the aging PDMSCs in the HA-coating surfaces, not only the cell morphology would change but also the cytoskeletons and endoplasmic reticulum (ER) type would also change, making the cells in a “less-aging” states. In additions, by using proteomics, the data demonstrated that some signaling pathways, including PI3K/AKT, RAS/RAF pathways, the expression of these proteins were higher in the HA-coating groups; while in HA coating group the expression level of downstream cell morphology-changing genes, phospho-cofilin and phospho-LIMK were lower. Besides, this research also used phospho-proteomics to observe which pathways were the phospho-proteins involved in. Also, this research used western blot to confirm the result whether it was the same as the result of proteomics. Total in this research, it showed that HA might affect the downstream signaling transduction and made PDMSCs had the effect of anti-aging.

References
Amorim, S., da Costa, D. S., Freitas, D., Reis, C. A., Reis, R. L., Pashkuleva, I., and Pires, R. A. Molecular weight of surface immobilized hyaluronic acid influences CD44-mediated binding of gastric cancer cells. Scientific Reports 8, 1-11, 2018.
Andreu, Z., Khan, M. A., González-Gómez, P., Negueruela, S., Hortigüela, R., Emeterio, J. S., Ferrón, S. R., Martínez, G., Vidal, A., Fariñas, I., Lie, D. C., and Mira, H. The Cyclin-Dependent Kinase Inhibitor p27kip1 Regulates Radial Stem Cell Quiescence and Neurogenesis in the Adult Hippocampus. Stem Cells 33, 219-229, 2015.
An, Z., Liu, P., Zheng, J., Si, C., Li, T., Chen, Y., and Ding, S. Sox2 and Klf4 as the Functional Core in Pluripotency Induction without Exogenous Oct4. Cell Reports 29, 1986-2000, 2019.
Arai, F., Hirao, A., Ohmura, M., Sato, H., Matsuoka, S., Takubo, K., Ito, K., Koh, G. Y., and Suda, T. Tie2/Angiopoietin-1 Signaling Regulates Hematopoietic Stem Cell Quiescence in the Bone Marrow Niche. Cell 118, 149-161, 2004.
Aruffo, A., Stamenkovic, I., Melnick, M., Underhill, C. B., and Seed, B. CD44 is the principal cell surface receptor for hyaluronate. Cell 61, 1303-1313, 1990.
Baker, D. J., Dawlaty, M. M., Wijshake, T., Jeganathan, K. B., Malureanu, L., Ree, J. H., Crespo-Diaz, R., Reyes, S., Seaburg, L., Shapiro, V., Behfar, A., Terzic, A., Sluis, B. V., and Deursen, J.M.V. Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. Nature Cell Biology 15, 96-102, 2013.
Behrens, A., Deursen, J. M. v., Rudolph, K. L., and Schumacher, B. Impact of genomic damage and ageing on stem cell function. Nature Cell Biology 16, 201-207, 2014.
Benham-Pyle, B. W., Pruitt, B. L., and Nelson, W. J. Mechanical strain induces E-cadherin–dependent Yap1 and β-catenin activation to drive cell cycle entry. Science 348, 1024-1027, 2015.
Bensaad, K., Tsuruta, A., Selak, M. A., Vidal, M. N., Nakano, K., Bartrons, R., Gottlieb, E., and Vousden, K. H. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126, 107-120, 2006.
Bishop, A. L., and Hall, A. Rho GTPases and their effector proteins. Biochemical Journal 348, 241-255, 2000.
Blau, H. M., Cosgrove, B. D., and Ho, A. T. V. The central role of muscle stem cells in regenerative failure with aging. Nature Medicine 21, 854-862, 2015.
Bourguignon, L. Y. W., Wong, G., Xia, W. L., Man, M. Q., Holleran, W. M., and Elias, P. M. Selective matrix (hyaluronan) interaction with CD44 and RhoGTPase signaling promotes keratinocyte functions and overcomes age-related epidermal dysfunction. Journal of Dermatological Science 72, 32-44, 2013.
Brown, M. K., and Naidoo, N. The endoplasmic reticulum stress response in aging and age-related diseases. Frontiers in Physiology 3, 1-10, 2012.
Brunauer, R., and Kennedy, B. K. Progeria accelerates adult stem cell aging. Science 348, 1093-1094, 2015.
Campisi, J., and Fagagna, F. d. A. d. Cellular senescence: when bad things happen to good cells. Nature Reviews Molecular Cell Biology 8, 729-740, 2007.
Chakkalakal, J. V., Jones, K. M., Basson, M. A., and Brack, A. S. The aged niche disrupts muscle stem cell quiescence. Nature 490, 355-360, 2012.
Chappell, W. H., Steelman, L. S., Long, J. M., Kempf, R. C., Abrams, S. L., Franklin, R. A., and Malaponte, G. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget 2, 135, 2011
Chen, C., Liu, Y., Liu, Y., and Zheng, P. mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells. Science 2, 75, 2009a.
Chen, C. C., and Lau, L. F. Functions and mechanisms of action of CCN matricellular proteins. International Journal of Biochemistry and Cell Biology 41, 771-783, 2009b.
Chen, Q. M., Tu, V. C., Catania, J., Burton, M., Toussaint, O., and Dilley, T. Involvement of Rb family proteins, focal adhesion proteins and protein synthesis in senescent morphogenesis induced by hydrogen peroxide. Journal of Cell Science 113, 4087-4097, 2000.
Cheng, J., Türkel, N., Hemati, N., Fuller, M. T., Hunt, A. J., and Yamashita, Y. M. Centrosome misorientation reduces stem cell division during ageing. Nature 456, 599-604, 2008.
Cheng, T., Rodrigues, N., Shen, H. M., Yang, Y. G., Dombkowski, D., Sykes, M., and Scadden, D. T. Hematopoietic Stem Cell Quiescence Maintained by p21cip1/waf1. Science 287, 1804-1808, 2000.
Cheung, T. H., and Rando, T. A. Molecular regulation of stem cell quiescence. Nature Reviews Molecular Cell Biology 14, 329-340, 2013.
Childs, B. G., Durik, M., Baker, D. J., and Deursen, J. M. v. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nature Medicine 21, 1424-1435, 2015.
Cho, K. A., Ryu, S. J., Oh, Y. S., Park, J. H., Lee, J. W., Kim, H. P., Kim, K. T., Jang, I. S., and Park, S. C. Morphological Adjustment of Senescent Cells by Modulating Caveolin-1 Status. Journal of Biological Chemistry 279, 42270-42278, 2004.
Chou, W. C., Takeo, M., Rabbani, P., Hu, H., Lee, W., Chung, Y. R., Carucci, J., Overbeek, P., and Ito, M. Direct migration of follicular melanocyte stem cells to the epidermis after wounding or UVB irradiation is dependent on Mc1r signaling. Nature Medicine 19, 924-929, 2013.

Choudhery, M. S., Badowski, M., Muise, A., Pierce, J., and Harris, D. T. Donor age negatively impacts adipose tissue-derived mesenchymal stem cell expansion and differentiation. Journal of Translational Medicine 12, 1112-1188, 2014.
Conboy, I. M., Conboy, M. J., Smythe, G. M., and Rando, T. A. Notch-Mediated Restoration of Regenerative Potential to Aged Muscle. Science 302, 1575-1577, 2003.
Conboy, I. M., Conboy, M. J., Wagers, A. J., Girma, E. R., Weissman, I. L., and Rando, T. A. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760-764, 2005.
Cristofalo, V. J., and Pignolo, R. J. Replicative senescence of human fibroblast-like cells in culture. Physiological Reviews 73, 617-638, 1993.
Damodarasamy, M., Johnson, R. S., Bentov, I., MacCoss, M. J., Vernon, R. B., and Reed, M. J. Hyaluronan enhances wound repair and increases collagen III in aged dermal wounds. Wound Repair and Regeneration 22, 521-526, 2014.
Darzynkiewicz, Z., and Balazs, E. A. Genome integrity, stem cells and hyaluronan. Aging 4, 78-88, 2012.
Das, R. K., Gocheva, V., Hammink, R., Zouani, O. F., and Rowan, A. E. Stress-stiffening-mediated stem-cell commitment switch in soft responsive hydrogels. Nature Materials 15, 318-325, 2016.
Dingal, P. C. D. P., and Discher, D. E. Combining insoluble and soluble factors to steer stem cell fate. Nature Materials 13, 532-537, 2013.
Dreesen, O., Chojnowski, A., Ong, P. F., Zhao, T. Y., Common, J. E., Lunny, D., Lane, E. B., Lee, S. J., Vardy, L. A., Stewart, C. L., and Colman, A. Lamin B1 fluctuations have differential effects on cellular proliferation and senescence. Journal of Cell Biology 200, 605-617, 2013.
Dumont, N. A., Wang, Y. X., and Rudnicki, M. A. Intrinsic and extrinsic mechanisms regulating satellite cell function. Development 142, 1572-1581, 2015.
Fafián-Labora, J., Fernández-Pernas, P., Fuentes, I., Toro, J. D., Oreiro, N., Sangiao-Alvarellos, S., Mateos, J., and Arufe, M. C. Influence of age on rat bone-marrow mesenchymal stem cells potential. Scientific Reports 5, 16765, 2015.
Flier, L. G. v. d., and Clevers, H. Stem Cells, Self-renewal, and differentiation in the intestinal epithelium. Annual Review of Physiology 71, 241-260, 2009.
Flores, I., Cayuela, M. L., and Blasco, M. A. Effects of telomerase and telomere length on epidermal stem cell behavior. Science 309, 1253-1256, 2005.
Florian, M. C., Nattamai, K. J., Dörr, K., Marka, G., Überle, B., Vas, V., Eckl, C., Andrä, I., Schiemann, M., Oostendorp, R. A. J., Scharffetter-Kochanek, K., Kestler, H. A., Zheng, Y., and Geiger, H. A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing. Nature 503, 392-396, 2013.
Folkman, J., and Moscona, A. Role of cell shape in growth control. Nature 273, 345-349, 1978.
Folmes, C. D. L., Dzeja, P. P., Nelson, T. J., and Terzic, A. Metabolic plasticity in stem cell homeostasis and differentiation. Cell Stem Cell 11, 596-606, 2012.
Fuchs, E., and Chen, T. A matter of life and death: self-renewal in stem cells. European Molecular Biology Organization Reports 14, 39-48, 2013.
Fuchs, E., Tumbar, T., and Guasch, G. Socializing with the Neighbors: Stem cells and their niche. Cell 116, 769-778, 2004.
Fukada, S. I., Uezumi, A., Ikemoto, M., Masuda, S., Segawa, M., Tanimura, N., Yamamoto, H., Suzuki, Y.M., and Takeda, S. Molecular signature of quiescent satellite cells in adult skeletal muscle. Stem Cells 25, 2448-2459, 2007.
Gattazzo, F., Urciuolo, A., and Bonaldo, P. Extracellular matrix: A dynamic micro-environment for stem cell niche. Biochimica et Biophysica Acta 1840, 2506-2519, 2014.
Geißler, S., Textor, M., Kühnisch, J., Könnig, D., Klein, O., Ode, A., Pfitzner, T., Adjaye, J., Kasper, G., and Duda, G. N. Functional Comparison of Chronological and In Vitro Aging: Differential Role of the Cytoskeleton and Mitochondria in Mesenchymal Stromal Cells. PLoS One 7, e52700, 2012.
Geiger, H., Haan, G. d., and Florian, M. C. The ageing haematopoietic stem cell compartment. Nature Reviews Immunology 13, 376-389, 2013.
Geiger, H., and Zant, G. V. The aging of lympho-hematopoietic stem cells. Nature Immunology 4, 329-333, 2002.
Gerecht, S., Burdick, J. A., Ferreira, L. S., Townsend, S. A., Langer, R., and Novakovic, G. V. Hyaluronic acid hydrogel for controlled self-renewal and differentiation of human embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America 104, 11298-11303, 2007.
Gharibi, B., Farzadi, S., Ghuman, M., and Hughes, F. J. Inhibition of Akt/mTOR attenuates age-related changes in mesenchymal stem cells. Stem Cells 32, 2256-2266, 2014.
Godar, S., Ince, T. A., Bell, G. W., Feldser, D., Donaher, J. L., Bergh, J., Liu, A., Miu, K., Watnick, R. S., Reinhardt, F., McAllister, S. S., Jacks, T., and Weinberg, R. A. Growth-inhibitory and tumor- suppressive functions of p53 depend on its repression of CD44 expression. Cell 134, 62-73, 2008.
Gogendeau, D., Siudeja, K., Gambarotto, D., Pennetier, C., Bardin, A. J., and Basto, R. Aneuploidy causes premature differentiation of neural and intestinal stem cells. Nature Communications 6, 8894, 2015.
Goodell, M. A., and Rando, T. A. Stem cells and healthy aging. Science 350, 1199-1204, 2015.
Gorbunova, V., Seluanov, A., Mao, Z. Y., and Hine, C. Changes in DNA repair during aging. Nucleic Acids Research 35, 7466-7474, 2007.
Gorovoy, M., Niu, J., Bernard, O., Profirovic, J., Minshall, R., Neamu, R., and Voyno-Yasenetskaya, T. LIM kinase 1 coordinates microtubule stability and actin polymerization in human endothelial cells. Journal of Biological Chemistry, 280, 26533-26542, 2005.
Goukassian, D., Gad, F., Yaar, M., Eller, M. S., Nehal, U. S., and Gilchrest, B. A. Mechanisms and implications of the age-associated decrease in DNA repair capacity. Federation of American Societies for Experimental Biology Journal 14, 1325-1334, 2000.
Gourlay, C. W., and Ayscough, K. R. Identification of an upstream regulatory pathway controlling actin-mediated apoptosis in yeast. Journal of Cell Science 118, 2119-2132, 2005.
Gregory, C. A., Ylostalo, J., and Prockop, D. J. Adult bone marrow stem/progenitor cells (MSCs) are preconditioned by microenvironmental "niches" in culture: a two-stage hypothesis for regulation of MSC fate. Science Signal Transduction Knowledge Environment 294, 37, 2005.
Hamant, O., Heisler, M. G., Jönsson, H., Krupinski, P., Uyttewaal, M., Bokov, P., Corson, F., Sahlin, P., Boudaoud, A., Meyerowitz, E. M., Couder, Y., and Traas, J. Developmental patterning by mechanical signals in arabidopsis. Science 322, 1650-1655, 2008.
Han, S. M., Han, S. H., Coh, Y. R., Jang, G., Ra, J. C., Kang, S. K., Lee, H. W., and Youn, H. Y. Enhanced proliferation and differentiation of Oct4- and Sox2-overexpressing human adipose tissue mesenchymal stem cells. Experimental and Molecular Medicine 46, 101, 2014.
Hanahan, D., and Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646-674, 2011.
Ho, J., and Bretscher, A. Ras Regulates the polarity of the yeast actin cytoskeleton through the stress response pathway. Molecular Biology of the Cell 12, 1541-1555, 2001.
Hobbs, R. M., Seandel, M., Falciatori, I., Rafii, S., and Pandolfi, P. P. Plzf regulates germline progenitor self-renewal by pposing mTORC1. Cell 142, 468-479, 2010.
Hong, W., Xu, X. Y., Qiu, Z. H., Gao, J. J., Wei, Z. Y., Zhen, L., Zhang, X. L., and Ye, Z. B. Sirt1 is involved in decreased bone formation in aged apolipoprotein E-deficient mice. Acta Pharmacologica Sinica 36, 1487-1496, 2015.
Horsley, V., Aliprantis, A. O., Polak, L., Glimcher, L. H., and Fuchs, E. NFATc1 Balances Quiescence and Proliferation of Skin Stem Cells. Cell 132, 299-310, 2008.
Huot, T. J., Rowe, J., Harland, M., Drayton, S., Brookes, S., Gooptu, C., Purkis, P., Fried, M., Bataille, V., Hara, E., Newton-Bishop, J., and Peters, G. Biallelic mutations in p16(INK4a) confer resistance to Ras- and Ets-induced senescence in human diploid fibroblasts. Molecular and Cell Biology 22, 8135-8143, 2002.
Hynes, R. O. The Extracellular Matrix: Not Just Pretty Fibrils. Science 326, 1216-1219, 2009.
Jackson, H. W., Waterhouse, P., Sinha, A., Kislinger, T., Berman, H. K., and Khokha, R. Expansion of stem cells counteracts age-related mammary regression in compound Timp1/Timp3 null mice. Nature Cell Biology 17, 217-227, 2015.
Jin, H. J., Kwon, J. H., Kim, M., Bae, Y. K., Choi, S. J., Oh, W., Yang, Y. S., and Jeon, H. B. Downregulation of melanoma cell adhesion molecule (MCAM/CD146) accelerates cellular senescence in human umbilical cord blood-derived mesenchymal stem cells. Stem Cells Translational Medicine 5, 427-439, 2016.
Jones, D. L., and Rando, T. A. Emerging models and paradigms for stem cell ageing. Nature Cell Biology 13, 506-512, 2011.
Jones, D. L., and Wagers, A. J. No place like home: anatomy and function of the stem cell niche. Nature Reviews Molecular Cell Biology 9, 11-21, 2008.
Jun, J. I., and Lau, L. F. Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets. Nature Reviewa Drug Discovery 10, 945-963, 2011.
Kai, T., and Spradling, A. An empty Drosophila stem cell niche reactivates the proliferation
of ectopic cells. Proceedings of the National Academy of Sciences of the United States of America 100, 4633-4638, 2003.
Kaushik, G., Spenlehauer, A., Sessions, A. O., Trujillo, A. S., Fuhrmann, A., Fu, Z., Venkatraman, V., Pohl, D., Tuler, J., Wang, M., Lakatta, E. G., Ocorr, K., Bodmer, R., Bernstein, S. I., Eyk, J. E. V., Cammarato, A., and Engler, A. J. Vinculin network-mediated cytoskeletal remodeling regulates contractile function in the aging heart. Science Translational Medicine 7, 292-299, 2015a.
Kaushik, S., and Cuervo, A. M. Proteostasis and aging. Nature Medicine 21, 1406-1415, 2015b.
Kevei, É., and Hoppe, T. Ubiquitin sets the timer: impacts on aging and longevity. Nature Structural and Molecular Biology 21, 290-292, 2014.
Kiger, A. A., Jones, D. L., Schulz, C., Rogers, M. B., and Fuller, M. T. Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue. Science 294, 2542-2545, 2001.
Kim, J., Park, Y., Tae, G., Lee, K. B., Hwang, C. M., Hwang, S. J., Kim, I. S., Noh, I., and Sun, K. Characterization of low-molecular-weight hyaluronic acid-based hydrogel and differential stem cell responses in the hydrogel microenvironments. Journal of Biomedical Materials Research Part A 88, 967-975, 2009.
Kim, K. S., Seu, Y. B., Baek, S. H., Kim, M. J., Kim, K. J., Kim, J. H., and Kim, J. R. Induction of cellular senescence by insulin-like growth factor binding protein-5 through a p53-dependent mechanism. Molecular Biology of the Cell 18, 4543-4552, 2007.
Kim, Y. T., Hur, E. M., Snider, W. D., and Zhou, F. Q. Role of GSK3 signaling in neuronal morphogenesis. Frontiers in Molecular Neuroscience 4, 48, 2010
Kishi, K., Okabe, K., Shimizu, R., and Kubota, Y. Fetal skin possesses the ability to regenerate completely: complete regeneration of skin. The Keio Journal of Medicine 61, 101-108, 2012.
Kobayashi, M., and Srour, E. F. Regulation of murine hematopoietic stem cell quiescence by Dmtf1. Blood 118, 6562-6571, 2011.
Korotchkina, L. G., Leontieva, O. V., Bukreeva, E. I., Demidenko, Z. N., Gudkov, A. V., and Blagosklonny, M. V. The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway. Aging 2, 344, 2010.
Kozutsumi, Y., Segal, M., Normington, K., Gething, M. J., and Sambrook, J. The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Cell 332, 462-464, 1988.
Kulterer, B., Friedl, G., Jandrositz, A., Cabo, F. S., Prokesch, A., Paar, C., Scheideler, M., Windhager, R., Preisegger, K. H., and Trajanoski, Z. Gene expression profiling of human mesenchymal stem cells derived from bone marrow during expansion and osteoblast differentiation. Biomed Central Genomics 8, 1188-1170, 2007.
Kuo, J. W. Practical Aspects of hyaluronan based medical products. Taylor and Francis, Boston, 2-19, 2005. Kwak, I. H., Kim, H. S., Choi, O. R., Ryu, M. S., and Lim, I. K. Nuclear accumulation of globular actin as a cellular senescence marker. Cancer Research 64, 572-580, 2004.
Kotiadis, V. N., Leadsham, J. E., Bastow, E. L., Gheeraert, A., Whybrew, J. M., Bard, M., and Gourlay, C. W. Identification of new surfaces of cofilin that link mitochondrial function to the control of multi-drug resistance. Journal of Cell Science 125, 2288-2299, 2012.
Lai, S. R., Phipps, S. M., Liu, L., Andrews, L. G., and Tollefsbol, T. O. Epigenetic control of telomerase and modes of telomere maintenance in aging and abnormal systems. Frontiers in Bioscience 10, 1779-1796, 2005.
Leadsham, J. E., Kotiadis, V. N., Tarrant, D. J., and Gourlay, C. W. Apoptosis and the yeast actin cytoskeleton. Cell Death and Differentiation 17, 754-762, 2010.
Lessard, J., and Sauvageau, G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423, 255-260, 2003.
Li, W., and Ding, S. Human pluripotent stem cells: decoding the naïve state. Science Translational Medicine 3, 10, 2011.
Lin, S., and Edward, J. C. An empirical protocol for whole-cell immunofluorescence of marine phytoplankton. Journal of Phycology 32, 1083-1094, 1996.
Lim, P. J., Danner, R., Liang, J., Doong, H., Harman, C., Srinivasan, D., Rothenberg, C., Wang, H., Ye, Y., Fang, S., and Monteiro, M. J. Ubiquilin and p97/VCP bind erasin, forming a complex involved in ERAD. Journal of Cell Biology 187, 201-217, 2009.
Litwiniuk, M., Krejner, A., Speyrer, M. S., Gauto, A. R., and Grzela, T. Hyaluronic acid in inflammation and tissue regeneration. Wounds, 28, 78-88, 2016.
Liu, C. M., Yu, C. H., Chang, C. H., Hsu, C. C., and Huang, L. L. H.. Hyaluronan substratum holds mesenchymal stem cells in slow-cycling mode by prolonging G1 phase. Cell Tissue Research 334, 435-443, 2008.
Liu, Y., Elf, S. E., Miyata, Y., Sashida, G., Liu, Y. H., Huang, G., Giandomenico, S. D., Lee, J. M., Deblasio, A., Menendez, S., Antipin, J., Reva, B., Koff, A., and Nimer, S. D. p53 regulates hematopoietic stem cell quiescence. Cell Stem Cell 4, 37-48, 2010.
Lugert, S., Basak, O., Knuckles, P., Haussler, U., Fabel, K., Götz, M., Haas, C., Kempermann, G., Taylor, V., and Giachino, C. Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging. Cell Stem Cell 6, 445-456, 2010.
Lutolf, M. P., and Hubbell, J. A. Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nature Biotechnology 23, 47-55, 2005.
Maharjan, A. S., Pilling, D., and Gomer, R. H. High and low molecular weight hyaluronic acid differentially regulate human fibrocyte differentiation. PLoS One 6, e26078, 2011.
Marschallinger, J., Schäffner, I., Klein, B., Gelfert, R., Rivera, F. J., Illes, S., Grassner, L., Janssen, M., Rotheneichner, P., Schmuckermair, C., Coras, R., Boccazzi, M., Chishty, M., Lagler, F. B., Renic, M., Bauer, H. C., Singewald, N., Blümcke, I., Bogdahn, U., Despres, S. C., Lie, D. C., Abbracchio, M. P., and Aigner, L. Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug. Nature Communications 6, 9466, 2015.
Martino, M. M., Briquez, P. S., Güç, E., Tortelli, F., Kilarski, W. W., Metzger, S., Rice, J. J., Kuhn, G. A., Müller, R., Swartz, M. A., and Hubbell, J. A. Growth factors engineered for super-affinity to the extracellular matrix enhance tissue healing. Science 343, 885-888, 2014.
Martelli, A. M., Evangelisti, C., Chiarini, F., and McCubrey, J. A. The phosphatidylinositol
3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. Oncotarget 1, 89, 2010.
Mayack, S. R., Shadrach, J. L., Kim, F. S., and Wagers, A. J. Systemic signals regulate ageing and rejuvenation of blood stem cell niches. Nature 463, 494-500, 2010.
McBeath, R., Pirone, D. M., Nelson, C. M., Bhadriraju, K., and Chen, C. S. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Developmental Cell 6, 483-495, 2004.
McCubrey, J. A., Abrams, S. L., Ligresti, G., Misaghian, N., Wong, E. W. T., Steelman, L. S., and Molton, S. Involvement of p53 and Raf/MEK/ERK pathways in hematopoietic drug resistance. Leukemia 22, 2080-2090, 2008.
Mizukami, H., Saitoh, S. I., Machii, H., Yamada, S., Hoshino, Y., Misaka, T., Ishigami, A., and Takeishi, Y. Senescence Marker Protein-30 (SMP30) Deficiency Impairs Myocardium-Induced Dilation of Coronary Arterioles Associated with Reactive Oxygen Species. International Journal of Molecular Sciences 14, 9408-9423, 2013.
Mohrin, M., Shin, J., Liu, Y., Brown, K., Luo, H., Xi, Y., Haynes, C. M., and Chen, D. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 347, 1374-1377, 2015.
Mohyeldin, A., Muvdi, T. G., and Hinojosa, A. Q. Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell 2010, 150-161, 2010.
Molofsky, A. V., He, S., Bydon, M., Morrison, S. J., and Pardal, R. Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes and Development 19, 1432-1437, 2005.
Moore, D. L., Pilz, G. A., Araúzo-Bravo, M. J., Barral, Y., and Jessberger, S. A mechanism for the segregation of age in mammalian neural stem cells. Science 349, 1334-1338, 2015.
Morrison, S. J., and Spradling, A. C. Stem Cells and Niches: Mechanisms That Promote Stem Cell Maintenance throughout Life. Cell 132, 598-611, 2008.
Mulder, B. On Growth and Force. Science 322, 1643-1644, 2008.
Murphy, W. L., McDevitt, T. C., and Engler, A. J. Materials as stem cell regulators. Nature Materials 13, 547-557, 2014.
Naidoo, N. ER and aging-Protein folding and the ER stress response. Ageing Research Reviews 8, 150-159, 2009.
Nijnik, A., Woodbine, L., Marchetti, C., Dawson, S., Lambe, T., Liu, C., Rodrigues, N. P., Crockford, T. L., Cabuy, E., Vindigni, A., Enver, T., Bell, J. I., Slijepcevic, P., Goodnow, C. C., Jeggo, P. A., and Cornall, R. J. DNA repair is limiting for haematopoietic stem cells during ageing. Nature 447, 686-690, 2007.
Nilsson, S. K., Haylock, D. N., Johnston, H. M., Occhiodoro, T., Brown, T. J., and Simmons, P. J. Hyaluronan is synthesized by primitive hemopoietic cells, participates in their lodgment at the endosteum following transplantation, and is involved in the regulation of their proliferation and differentiation in vitro. Blood 101, 856-862, 2003.
Nishimura, E. K., Granter, S. R., and Fisher, D. E. Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science 307, 720-724, 2005.
Nusgens, B. V. Hyaluronic acid and extracellular matrix: a primitive molecule? Annales de Dermatologie et de Vénéréologie 137, 70002-70008, 2010.
Oakley, E. J., and Zant, G. V. Unraveling the complex regulation of stem cells: implications for aging and cancer. Leukemia 21, 612-621, 2007.
Oesterle, E. C., Chien, W. M., Campbell, S., Nellimarla, P., and Fero, M. L. p27Kip1 is required to maintain proliferative quiescence in the adult cochlea and pituitary. Cell Cycle 10, 1237-1248, 2011.
Oh, J., Lee, Y. D., and Wagers, A. J. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nature Medicine 20, 870-880, 2014.
Os, R. v., Haan, G. d., and Dykstra, B. J. Hematopoietic stem cell quiescence: yet another role for p53. Cell Stem Cell 4, 7-8, 2009.
Pan, L., Chen, S., Weng, C., Call, G., Zhu, D., Tang, H., Zhang, N., and Xie, T. Stem cell aging is controlled both intrinsically and extrinsically in the Drosophila ovary. Cell Stem Cell 1, 458-469, 2007.
Park, Y., and Gerson, S. L. DNA repair defects in stem cell function and aging. Annual Review of Medicine 56, 495-508, 2005.
Pollina, E. A., and Brunet, A. Epigenetic regulation of aging stem cells. Oncogene 30, 3105-3126, 2011.
Priddle, H., Hemmings, L., Monkley, S., Woods, A., Patel, B., Sutton, D., Dunn, G. A., Zicha, D., and Critchley, D. R. Disruption of the talin gene compromises focal adhesion assembly in undifferentiated but not differentiated embryonic stem cells. Journal of Cell Biology 142, 1121-1133, 1998.
Puzio-Kuter, A. M. The Role of p53 in metabolic regulation. Genes Cancer 2, 385-391, 2011.
Röck, K., Tigges, J., Sass, S., Schütze, A., Florea, A. M., Fender, A. C., Theis, F. J., Krutmann, J., Boege, F., Fritsche, E., Reifenberger, G., and Fischer, J. W. miR-23a-3p causes cellular senescence by targeting hyaluronan synthase 2: possible implication for skin aging. Journal of Investigative Dermatology 135, 369-377, 2015.
Ramos, H. V. L., Neves, L. R., Martins, J. R. M., Nader, H. B., and Pontes, P. Influence of aging on hyaluronic acid concentration in the vocal folds of female rats. Brazilian Journal of Otorhinolaryngology 78, 14-18, 2012.
Rando, T. A. Stem cells, ageing and the quest for immortality. Nature 441, 1080-1086, 2006.
Rando, T. A., and Chang, H. Y. Aging, Rejuvenation, and Epigenetic Reprogramming: Resetting the Aging Clock. Cell 148, 46-57, 2012.
Reed, S. M., and Quelle, D. E. p53 Acetylation: Regulation and Consequences. Cancers 7, 30-69, 2015.
Reya, T., Morrison, S. J., Clarke, M. F., and Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105-111, 2001.
Riento, K., and Ridley, A. J. Rocks: multifunctional kinases in cell behaviors. Nature Reviews Molecular Cell Biology, 4, 446-456, 2003.
Riessen, R., Wight, T. N., Pastore, C., Henley, C., and Isner, J. M. Distribution of Hyaluronan
During Extracellular Matrix Remodeling in Human Restenotic Arteries and Balloon-Injured Rat Carotid Arteries. Circulation 93, 1141-1147 1996.
Rodier, G., Montagnoli, A., Marcotullio, L. D., Coulombe, P., Draetta, G. F., Pagano, M., and Meloche, S. p27 cytoplasmic localization is regulated by phosphoylation on Ser10 and is not a prerequisite for its proteolysis. European Molecular Biology Organization Journal 20, 6672-6682, 2001.
Rossi, D. J., Bryder, D., Seita, J., Nussenzweig, A., Hoeijmakers, J., and Weissman, I. L. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447, 725-729, 2007.
Rossi, D. J., and Weissman, I. L. Pten, tumorigenesis, and stem cell self-renewal. Cell 125, 229-231, 2006.
Ruan, M. Z. C., Erez, A., Guse, K., Dawson, B., Bertin, T., Chen, Y., Jiang, M. M., Yustein, J., Gannon, F., and Lee, B. H. L. Proteoglycan 4 expression protects against the development of osteoarthritis. Science Translational Medicine 5, 176ra34, 2013.
Rubin, H. Cell aging in vivo and in vitro. Mechanisms of Ageing and Development 98, 1-35, 1997.
Safrankova, B., Gajdova, S., and Kubala, L. The potency of hyaluronan of different molecular weights in the stimulation of blood phagocytes. Mediators of Inflammation 2010, 380948, 2010.
Sawada, R., Ito, T., and Tsuchiya, T. Changes in expression of genes related to cell proliferation in human mesenchymal stem cells during in vitro culture in comparison with cancer cells. Journal of Artificial Organs 9, 179-184, 2006.
Schmidt, B. A., and Horsley, V. Intradermal adipocytes mediate fibroblast recruitment during skin wound healing. Development 140, 1517-1527, 2013.
Schulz, Y., Anthropology, M., and Law, M. Time representations in social science. Dialogues in Clinical Neuroscience 14, 441-447, 2012.
Sennett, R., and Rendl, M. A scar is born: Origins of fibrotic skin tissue. Science 348, 284-285, 2015.
Sharpless, N. E., and DePinho, R. A. How stem cells age and why this makes us grow old. Nature Reviews Molecular Cell Biology 8, 703-713, 2007.
Shizuru, J. A., Negrin, R. S., and Weissman, I. L. Hematopoietic stem and progenitor cells:
clinical and preclinical regeneration of the hematolymphoid system. Annual Review of Medicine 56, 509-538, 2005.
Shukla, S., Nair, R., Rolle, M. W., Braun, K. R., Chan, C. K., Johnson, P. Y., Wight, T. N., and McDevitt, T. C. Synthesis and organization of hyaluronan and versican by embryonic stem cells undergoing embryoid body differentiation. Journal of Histochemistry and Cytochemistry 58, 345-358, 2010.
Simpson, R. M. L., Wells, A., Thomas, D., Stephens, P., Steadman, R., and Phillips, A. Aging fibroblasts resist phenotypic maturation because of impaired hyaluronan-dependent CD44/epidermal growth factor receptor signaling. The American Journal of Pathology 176, 1215-1228, 2010.
Solis, M. A., Chen, Y. H., Wong, T. Y., Bittencourt, V. Z., Lin, Y. C., and Huang, L. L. H. Hyaluronan regulates cell behavior: a potential niche matrix for stem cells. Biochemistry Research International 2012, 346972, 2012.
Son, T. G., Park, H. R., Kim, S. J., Kim, K., Kim, M. S., Ishigami, A., Handa, S., Maruyama, N., Chung, H. Y., and Lee, J. Senescence marker protein 30 is up-regulated in kainate-induced hippocampal damage through ERK-mediated astrocytosis. Journal of Neuroscience Research 87, 2890-2897, 2009.
Spangrude, G. J., Heimfeld, S., and Weissman, I. L. Purification and characterization of mouse hematopoietic stem cells. Science 241, 58-62, 1988.
Spradling, A., Barbosa, D. D., and Kai, T. Stem cells find their niche. Nature 414, 98-104, 2001.
Susaki, E., Nakayama, K., and Nakayama, K. I. Cyclin D2 Translocates p27 out of the nucleus and promotes its degradation at the G0-G1 transition. Molecular Cell Biology 27, 4626-4640, 2007.
Suwan, K., Choocheep, K., Hatano, S., Kongtawelert, P., Kimata, K., and Watanabe, H. Versican/PG-M assembles hyaluronan into extracellular matrix and inhibits CD44-mediated signaling toward premature senescence in embryonic fibroblasts. The Journal of Biological Chemistry 284, 8596-8604, 2009.
Takai, Y., Sasaki, T., and Matozaki, T. Small GTP-binding proteins. Physiological Reviews 81, 153-208, 2001.
Tsai, C. H., and Lee, Y. J. Focus on ADF/Cofilin: beyond actin Cytoskeletal regulation. Cell Biology 2012, 597876, 2012.
Todorovicç, V., Chen, C. C., Hay, N., and Lau, L. F. The matrix protein CCN1 (CYR61) induces apoptosis in fibroblasts. Journal of Cell Biology 171, 559-568, 2005.
Tzircotis, G., Thorne, R. F., and Isacke, C. M. Chemotaxis towards hyaluronan is dependent on CD44 expression and modulated by cell type variation in CD44-hyaluronan binding. Journal of Cell Science 118, 5119-5128, 2005.
Vicente, M. M., Sovak, G., and Cuervo, A. M. Protein degradation and aging. Experimental Gerontology 40, 622-633, 2005.
Villeda, S. A., Plambeck, K. E., Middeldorp, J., Castellano, J. M., Mosher, K. I., Luo, J., Smith, L. K., Bieri, G., Lin, K., Berdnik, D., Wabl, R., Udeochu, J., Wheatley, E. G., Zou, B., Simmons, D. A., Xie, X. S., Longo, F. M., and Coray, T. W. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature Medicine 20, 659-663, 2014.
Wabnitz, G. H., Nebl, G., Klemke, M., Schröder, A. J., and Samstag, Y. Phosphatidylinositol 3-kinase functions as a Ras effector in the signaling cascade that regulates dephosphorylation of the actin-remodeling protein cofilin after costimulation of untransformed human T lymphocytes. The Journal of Immunology 176, 1668-1674, 2006
Wagnera, W., Horna, P., Borka, S., and Ho, A. D. Aging of hematopoietic stem cells is regulated by the stem cell niche. Experimental Gerontology 43, 974-980, 2008.
Wakabayashi, S., and Yoshida, H. The essential biology of the endoplasmic reticulum stress response for structural and computational biologists. Computational and Structural Biotechnology Journal 6, e201303010, 2013.
Wang, J. C. Y., Warner, J. K., Erdmann, N., Lansdorp, P. M., Harrington, L., and Dick, J. E. Dissociation of telomerase activity and telomere length maintenance in primitive human hematopoietic cells. Proceedings of the National Academy of Sciences of the United States of America 107, 14398-14403, 2005.
Wang, H., Lee, E. W., Cai, X., Ni, Z., Zhou, L., and Mao, Q. Membrane topology of the human breast cancer resistance protein (BCRP/ABCG2) determined by epitope insertion and immunofluorescence. Biochemistry 47, 13778-13787, 2008.
Wasserman, S. A., and DiNardo, S. Staying a boy forever. Science 294, 2495-2497, 2001.
Watt, F. M., and Hogan, B. L. M. Out of eden: Stem cells and their niches. Science 287, 1427-1430, 2000.
Watt, F. M., and Huck, W. T. S. Role of the extracellular matrix in regulating stem cell fate. Nature Reviews Molecular Cell Biology 14, 467-473, 2013.
Wong, T. Y., Chen, Y. H., Liu, S. H., Solis, M. A., Yu, C. H., Chang, C. H., and Huang, L. L. H. Differential Proteomic Analysis of Human Placenta Derived Mesenchymal Stem Cells Cultured on Normal Tissue Culture Surface and Hyaluronan. Stem Cells International 2016, 1-16, 2016.
Wu, S. C., Chang, J. K., Wang, C. K., Wang, G. J., and Ho, M. L. Enhancement of chondrogenesis of human adipose derived stem cells in a hyaluronan-enriched microenvironment. Biomaterials 31, 631-640, 2010.
Xi, R., and Xie, T. Stem cell self-renewal controlled by chromatin remodeling factors. Science 310, 1487-1489, 2005.
Xie, C. F., Jin, J. L., Lv, X. H., Tao, J. G., Wang, R., and Miao, D. S. Anti-aging effect of transplanted amniotic membrane mesenchymal stem cells in a premature aging model of Bmi-1 deficiency. Scientific Reports 5, 13975, 2015.
Xie, H., Tang, C. H. A., Song, J. H., Mancuso, A., Del Valle, J. R., Cao, J., and Keith, B. IRE1α RNase–dependent lipid homeostasis promotes survival in Myc-transformed cancers. The Journal of Clinical Investigation 128, 1300-1316, 2018.
Yamazaki, S., Ema, H., Karlsson, G., Yamaguchi, T., Miyoshi, H., Shioda, S., Taketo, M. M., Karlsson, S., Iwama, A., and Nakauchi, H. Non-myelinating schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 147, 1146-1158, 2011.
Yielding, K. L., Tomkins, G. M., and Bunim, J. J. Synthesis of hyaluronic acid by human synovial tissue slices. Science 125, 1300, 1957.
Yu, Z., Luo, H., Fu, W., and Mattson, M. P. The endoplasmic reticulum stress-responsive protein GRP78 protects neurons against excitotoxicity and apoptosis: suppression of oxidative stress and stabilization of calcium homeostasis. Experimental Neurology 155, 302-314, 1999.
Yoshimura, T., Kawano, Y., Arimura, N., Kawabata, S., Kikuchi, A., and Kaibuchi, K. GSK-3β regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120, 137-149, 2005.
Zhu, A. J., and Watt, F. M. Beta-catenin signalling modulates proliferative potential of human epidermal keratinocytes independently of intercellular adhesion. Development 126, 2285-2298, 1999.
Zhou, Y., Zhou, b., Panche, L., Chang, M., Khodabakhshi, A.H, Tanaseichuk, O., Benner,
C. and Chanda, S.K. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nature Communications 10, 1-10, 2019.