Uncovering the dual role of RHAMM as an HA receptor and a regulator of CD44 expression in RHAMM-expressing mesenchymal progenitor cells

Veiseh, Mandana; Leith, Sean J.; Tolg, Cornelia; Elhayek, Sallie S.; Bahrami, S. Bahram; Collis, Lisa; Hamilton, Sara; McCarthy, James B.; Bissell, Mina J.; Turley, Eva

doi:10.3389/fcell.2015.00063

Uncovering the dual role of RHAMM as an HA receptor and a regulator of CD44 expression in RHAMM-expressing mesenchymal progenitor cells

Journal Article · Thu Oct 15 00:00:00 EDT 2015 · Frontiers in Cell and Developmental Biology

DOI:https://doi.org/10.3389/fcell.2015.00063· OSTI ID:1629220

Veiseh, Mandana ^[1]; Leith, Sean J. ^[2]; Tolg, Cornelia ^[2]; Elhayek, Sallie S. ^[2]; Bahrami, S. Bahram ^[3]; Collis, Lisa ^[2]; Hamilton, Sara ^[2]; McCarthy, James B. ^[4]; Bissell, Mina J. ^[3]; Turley, Eva ^[2]

Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division; Palo Alto Research Center Incorporated, Palo Alto, CA (United States); DOE/OSTI
Western Univ., London, ON (Canada). London Regional Cancer Program. Western Schulich School of Medicine. Dept. of Oncology/Biochemistry/Surgery
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division
Univ. of Minnesota, Minneapolis, MN (United States). Masonic Comprehensive Cancer Center. Dept. of Lab. Medicine and Pathology

The interaction of hyaluronan (HA) with mesenchymal progenitor cells impacts trafficking and fate after tissue colonization during wound repair and these events contribute to diseases such as cancer. How this interaction occurs is poorly understood. Using 10T½ cells as a mesenchymal progenitor model and fluorescent (F-HA) or gold-labeled HA (G-HA) polymers, we studied the role of two HA receptors, RHAMM and CD44, in HA binding and uptake in non-adherent and adherent mesenchymal progenitor (10T½) cells to mimic aspects of cell trafficking and tissue colonization. We show that fluorescent labeled HA (F-HA) binding/uptake was high in non-adherent cells but dropped over time as cells became increasingly adherent. Non-adherent cells displayed both CD44 and RHAMM but only function-blocking anti-RHAMM and not anti-CD44 antibodies significantly reduced F-HA binding/uptake. Adherent cells, which also expressed CD44 and RHAMM, primarily utilized CD44 to bind to F-HA since anti-CD44 but not antiRHAMM antibodies blocked F-HA uptake. RHAMM overexpression in adherent 10T½ cells led to increased F-HA uptake but this increased binding remained CD44 dependent. Further studies showed that RHAMM-transfection increased CD44 mRNA and protein expression while blocking RHAMM function reduced expression. Collectively, these results suggest that cellular microenvironments in which these receptors function as HA binding proteins differ significantly, and that RHAMM plays at least two roles in FHA binding by acting as an HA receptor in non-attached cells and by regulating CD44 expression and display in attached cells. Our findings demonstrate adhesion-dependent mechanisms governing HA binding/ uptake that may impact development of new mesenchymal cell-based therapies.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1629220

Journal Information:: Frontiers in Cell and Developmental Biology, Journal Name: Frontiers in Cell and Developmental Biology Vol. 3; ISSN 2296-634X

Publisher:: Frontiers Media S.A.Copyright Statement

Country of Publication:: United States

Language:: English

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Hyaluronan in the Healthy and Malignant Hematopoietic Microenvironment Khaldoyanidi, Sophia K.; Goncharova, Valentina; Mueller, Barbara Advances in Cancer Research https://doi.org/10.1016/B978-0-12-800092-2.00006-X	book	January 2014
Hyaluronan Regulation of Endothelial Barrier Function in Cancer Singleton, Patrick A. Advances in Cancer Research https://doi.org/10.1016/B978-0-12-800092-2.00007-1	book	January 2014
Hyaluronan–CD44 Interaction Promotes Oncogenic Signaling, microRNA Functions, Chemoresistance, and Radiation Resistance in Cancer Stem Cells Leading to Tumor Progression Bourguignon, Lilly Y. W.; Shiina, Marisa; Li, Jian-Jian Advances in Cancer Research https://doi.org/10.1016/B978-0-12-800092-2.00010-1	book	January 2014
Hyaluronan/RHAMM Interactions in Mesenchymal Tumor Pathogenesis Kouvidi, Katerina; Nikitovic, Dragana; Berdiaki, Aikaterini Advances in Cancer Research https://doi.org/10.1016/B978-0-12-800092-2.00012-5	book	January 2014
Rapid hyaluronan uptake is associated with enhanced motility: implications for an intracellular mode of action Collis, L.; Hall, C.; Lange, L. FEBS Letters, Vol. 440, Issue 3 https://doi.org/10.1016/S0014-5793(98)01505-1	journal	December 1998
Altered Hyaluronan Biosynthesis in Cancer Progression Itano, Naoki; Kimata, Koji Hyaluronan in Cancer Biology https://doi.org/10.1016/b978-012374178-3.10010-9	book	January 2009
MSCs and hyaluronan: Sticking together for new therapeutic potential? Kota, Daniel J.; Prabhakara, Karthik S.; Cox, Charles S. The International Journal of Biochemistry & Cell Biology, Vol. 55 https://doi.org/10.1016/j.biocel.2014.07.022	journal	October 2014
Altered hyaluronan biosynthesis in cancer progression Itano, Naoki; Kimata, Koji Seminars in Cancer Biology, Vol. 18, Issue 4 https://doi.org/10.1016/j.semcancer.2008.03.006	journal	August 2008
The High and Low Molecular Weight Forms of Hyaluronan Have Distinct Effects on CD44 Clustering Yang, Cuixia; Cao, Manlin; Liu, Hua Journal of Biological Chemistry, Vol. 287, Issue 51 https://doi.org/10.1074/jbc.M112.349209	journal	November 2012
Toll-like Receptor 2 (TLR2), Transforming Growth Factor-β, Hyaluronan (HA), and Receptor for HA-mediated Motility (RHAMM) Are Required for Surfactant Protein A-stimulated Macrophage Chemotaxis Foley, Joseph P.; Lam, David; Jiang, Hongmei Journal of Biological Chemistry, Vol. 287, Issue 44 https://doi.org/10.1074/jbc.M112.360982	journal	September 2012
Hyaluronan and Layilin Mediate Loss of Airway Epithelial Barrier Function Induced by Cigarette Smoke by Decreasing E-cadherin Forteza, Rosanna Malbran; Casalino-Matsuda, S. Marina; Falcon, Nieves S. Journal of Biological Chemistry, Vol. 287, Issue 50 https://doi.org/10.1074/jbc.M112.387795	journal	October 2012
Acylation of CD44 and Its Association with Lipid Rafts Are Required for Receptor and Hyaluronan Endocytosis Thankamony, Sai P.; Knudson, Warren Journal of Biological Chemistry, Vol. 281, Issue 45 https://doi.org/10.1074/jbc.M601530200	journal	August 2006
The Hyaluronan Receptors CD44 and Rhamm (CD168) Form Complexes with ERK1,2 That Sustain High Basal Motility in Breast Cancer Cells Hamilton, Sara R.; Fard, Shireen F.; Paiwand, Frouz F. Journal of Biological Chemistry, Vol. 282, Issue 22 https://doi.org/10.1074/jbc.M702078200	journal	March 2007
Transforming Growth Factor-β (TGF-β1) Down-regulates Notch3 in Fibroblasts to Promote Smooth Muscle Gene Expression Kennard, Simone; Liu, Hua; Lilly, Brenda Journal of Biological Chemistry, Vol. 283, Issue 3 https://doi.org/10.1074/jbc.M706651200	journal	November 2007
Complexity of Danger: The Diverse Nature of Damage-associated Molecular Patterns Schaefer, Liliana Journal of Biological Chemistry, Vol. 289, Issue 51 https://doi.org/10.1074/jbc.R114.619304	journal	November 2014
The high and low molecular weight forms of hyaluronan have distinct effects on CD44 clustering. Yang, Cuixia; Cao, Manlin; Liu, Hua Journal of Biological Chemistry, Vol. 288, Issue 46 https://doi.org/10.1074/jbc.a112.349209	journal	November 2013
The Hyaluronan Synthesis Inhibitor 4-Methylumbelliferone Prevents Keratinocyte Activation and Epidermal Hyperproliferation Induced by Epidermal Growth Factor Rilla, Kirsi; Pasonen-Seppänen, Sanna; Rieppo, Jarno Journal of Investigative Dermatology, Vol. 123, Issue 4 https://doi.org/10.1111/j.0022-202X.2004.23409.x	journal	October 2004
The Roles of Hyaluronan/RHAMM/CD44 and Their Respective Interactions along the Insidious Pathways of Fibrosarcoma Progression Nikitovic, Dragana; Kouvidi, Katerina; Karamanos, Nikos K. BioMed Research International, Vol. 2013 https://doi.org/10.1155/2013/929531	journal	January 2013
ERK1/2 Regulation of CD44 Modulates Oral Cancer Aggressiveness Judd, N. P.; Winkler, A. E.; Murillo-Sauca, O. Cancer Research, Vol. 72, Issue 1 https://doi.org/10.1158/0008-5472.CAN-11-1831	journal	November 2011
Functional Heterogeneity of Cancer-Associated Fibroblasts from Human Colon Tumors Shows Specific Prognostic Gene Expression Signature Herrera, M.; Islam, A. B. M. M. K.; Herrera, A. Clinical Cancer Research, Vol. 19, Issue 21 https://doi.org/10.1158/1078-0432.CCR-13-0694	journal	September 2013
Influence of Nanoparticle Shape, Size, and Surface Functionalization on Cellular Uptake Ma, Ningning; Ma, Chao; Li, Chuanyan Journal of Nanoscience and Nanotechnology, Vol. 13, Issue 10 https://doi.org/10.1166/jnn.2013.7525	journal	October 2013
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Myostatin promotes a fibrotic phenotypic switch in multipotent C3H 10T1/2 cells without affecting their differentiation into myofibroblasts Artaza, Jorge N.; Singh, Rajan; Ferrini, Monica G. Journal of Endocrinology, Vol. 196, Issue 2 https://doi.org/10.1677/JOE-07-0408	journal	November 2007
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Fetal Skin Possesses the Ability to Regenerate Completely: Complete Regeneration of Skin Kishi, Kazuo; Okabe, Keisuke; Shimizu, Ruka The Keio Journal of Medicine, Vol. 61, Issue 4 https://doi.org/10.2302/kjm.2011-0002-IR	journal	January 2012
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Hyaluronan, Cancer-Associated Fibroblasts and the Tumor Microenvironment in Malignant Progression McCarthy, James B.; El-Ashry, Dorraya; Turley, Eva A. Frontiers in Cell and Developmental Biology, Vol. 6 https://doi.org/10.3389/fcell.2018.00048	journal	May 2018

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