Zinc Promotes Adipose-Derived Mesenchymal Stem Cell Proliferation and Differentiation towards a Neuronal Fate

Zinc is an essential element required for cell division, migration, and proliferation. Under zinc-deficient conditions, proliferation and differentiation of neural progenitors are significantly impaired. Adipose-derived mesenchymal stem cells (AD-MSCs) are multipotent stem cells that can differentiate into neurons. The aim of this study was to evaluate the effect of zinc on AD-MSC proliferation and differentiation. We initially examined the effect of zinc on stem cell proliferation at the undifferentiated stage. AD-MSCs showed high proliferation rates on day 6 in 30 μM and 100 μM of ZnCl2. Zinc chelation inhibited AD-MSC proliferation via downregulation of ERK1/2 activity. We then assessed whether zinc was involved in cell migration and neurite outgrowth during differentiation. After three days of neuronal differentiation, TUJ-1-positive cells were observed, implying that AD-MSCs had differentiated into early neuron or neuron-like cells. Neurite outgrowth was increased in the zinc-treated group, while the CaEDTA-treated group showed diminished, shrunken neurites. Furthermore, we showed that zinc promoted neurite outgrowth via the inactivation of RhoA and led to the induction of neuronal gene expression (MAP2 and nestin) in differentiated stem cells. Taken together, zinc promoted AD-MSC proliferation and affected neuronal differentiation, mainly by increasing neurite outgrowth.

[1]  P. Adlard,et al.  Zinc Signal in Brain Diseases , 2017, International journal of molecular sciences.

[2]  P. Oteiza,et al.  Gestational marginal zinc deficiency impaired fetal neural progenitor cell proliferation by disrupting the ERK1/2 signaling pathway. , 2015, The Journal of nutritional biochemistry.

[3]  S. Suh,et al.  Adipose‐Derived Mesenchymal Stem Cells Reduce Neuronal Death After Transient Global Cerebral Ischemia Through Prevention of Blood‐Brain Barrier Disruption and Endothelial Damage , 2015, Stem cells translational medicine.

[4]  H. Liu,et al.  Investigation of magnesium-zinc-calcium alloys and bone marrow derived mesenchymal stem cell response in direct culture. , 2015, Acta biomaterialia.

[5]  S. Razavi,et al.  Effect of T3 hormone on neural differentiation of human adipose derived stem cells , 2014, Cell biochemistry and function.

[6]  Bo Eun Lee,et al.  Zinc chelation reduces traumatic brain injury-induced neurogenesis in the subgranular zone of the hippocampal dentate gyrus. , 2014, Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements.

[7]  J. Rhie,et al.  Adipose Tissue Regeneration In Vivo Using Micronized Acellular Allogenic Dermis as an Injectable Scaffold , 2014, Aesthetic Plastic Surgery.

[8]  J. Verdi,et al.  Citalopram increases the differentiation efficacy of bone marrow mesenchymal stem cells into neuronal-like cells , 2014, Neural regeneration research.

[9]  C. Keen,et al.  Neurulation and neurite extension require the zinc transporter ZIP12 (slc39a12) , 2013, Proceedings of the National Academy of Sciences.

[10]  Rikki S. Corniola,et al.  Zinc deficiency regulates hippocampal gene expression and impairs neuronal differentiation , 2013, Nutritional neuroscience.

[11]  J. Feldmann,et al.  Long-term zinc deprivation accelerates rat vascular smooth muscle cell proliferation involving the down-regulation of JNK1/2 expression in MAPK signaling. , 2013, Atherosclerosis.

[12]  S. Suh,et al.  Zinc Chelation Reduces Hippocampal Neurogenesis after Pilocarpine-Induced Seizure , 2012, PloS one.

[13]  M. Miloso,et al.  Expression of Neural Markers by Undifferentiated Rat Mesenchymal Stem Cells , 2012, Journal of biomedicine & biotechnology.

[14]  Hyoung‐Chun Kim,et al.  Control of neurite outgrowth by RhoA inactivation , 2012, Journal of neurochemistry.

[15]  P. Oteiza,et al.  Zinc and the ERK Kinases in the Developing Brain , 2011, Neurotoxicity Research.

[16]  V. Tkachuk,et al.  Adipose-Derived Stem Cells Stimulate Regeneration of Peripheral Nerves: BDNF Secreted by These Cells Promotes Nerve Healing and Axon Growth De Novo , 2011, PLoS ONE.

[17]  J. M. Ryu,et al.  Involvement of caveolin‐1 in fibronectin‐induced mouse embryonic stem cell proliferation: Role of FAK, RhoA, PI3K/Akt, and ERK 1/2 pathways , 2011, Journal of cellular physiology.

[18]  D. Lovley,et al.  Purification and Characterization of OmcZ, an Outer-Surface, Octaheme c-Type Cytochrome Essential for Optimal Current Production by Geobacter sulfurreducens , 2010, Applied and Environmental Microbiology.

[19]  C. Sheline,et al.  Decreased Brain Zinc Availability Reduces Hippocampal Neurogenesis in Mice and Rats , 2009, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[20]  D. Bonatto,et al.  Differentiation of human adipose-derived adult stem cells into neuronal tissue: does it work? , 2009, Differentiation; research in biological diversity.

[21]  Rikki S. Corniola,et al.  Zinc deficiency impairs neuronal precursor cell proliferation and induces apoptosis via p53-mediated mechanisms , 2008, Brain Research.

[22]  A. Sbarbati,et al.  Neuronal differentiation potential of human adipose-derived mesenchymal stem cells. , 2008, Stem cells and development.

[23]  G. Rico-Rosillo,et al.  Effect of Zinc Upon Human and Murine Cell Viability and Differentiation , 2007, Biological Trace Element Research.

[24]  H. Deng,et al.  MEK/ERK signaling contributes to the maintenance of human embryonic stem cell self-renewal. , 2007, Differentiation; research in biological diversity.

[25]  W. Maret,et al.  Zinc requirements and the risks and benefits of zinc supplementation. , 2006, Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements.

[26]  S. Perez,et al.  Characterization of the Optimal Culture Conditions for Clinical Scale Production of Human Mesenchymal Stem Cells , 2006, Stem cells.

[27]  M. Hedrick,et al.  Multipotential differentiation of adipose tissue-derived stem cells. , 2005, The Keio journal of medicine.

[28]  Hongjun Song,et al.  Adult neurogenesis in the mammalian central nervous system. , 2005, Annual review of neuroscience.

[29]  P. Weinstein,et al.  Hypoglycemia induces transient neurogenesis and subsequent progenitor cell loss in the rat hippocampus. , 2005, Diabetes.

[30]  Y. Bae,et al.  Characterization and Expression Analysis of Mesenchymal Stem Cells from Human Bone Marrow and Adipose Tissue , 2004, Cellular Physiology and Biochemistry.

[31]  D. Coulter,et al.  Clioquinol effects on tissue chelatable zinc in mice , 2003, Journal of Molecular Medicine.

[32]  A. Manira,et al.  Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[33]  I. Black,et al.  Adult rat and human bone marrow stromal cells differentiate into neurons , 2000, Journal of neuroscience research.

[34]  G. Danscher,et al.  Zinc-enriched (ZEN) terminals in mouse spinal cord: immunohistochemistry and autometallography , 2000, Brain Research.

[35]  R. Macdonald.  The role of zinc in growth and cell proliferation. , 2000, The Journal of nutrition.

[36]  J. G. Penland,et al.  History of zinc as related to brain function. , 2000, The Journal of nutrition.

[37]  J. Szeberényi,et al.  Different Roles for RhoA During Neurite Initiation, Elongation, and Regeneration in PC12 Cells , 1999, Journal of neurochemistry.

[38]  G. Danscher,et al.  Intravesicular localization of zinc in rat telencephalic boutons. A histochemical study , 1985, Brain Research.

[39]  H. Sandstead,et al.  Alterations in the postnatal development of the cerebellar cortex due to zinc deficiency. II. Impaired maturation of Purkinje cells. , 1984, Brain research.

[40]  G. A. Howell,et al.  Cholinergic denervation-induced increase of chelatable zinc in mossy-fiber region of the hippocampal formation , 1984, Brain Research.