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			<p class="Type-of-Article">&nbsp;</p>
			<p class="Type-of-Article"><span class="CharOverride-1">Review Article</span></p>
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		<div class="Basic-Text-Frame">
			<p class="title- ParaOverride-1">&nbsp;</p>
			<p class="title- ParaOverride-1">Concise Review: Appreciated Signaling Role of High Mobility Group–A Proteins for Regulation of Proliferation, Pluripotency and Self-Renewal of Adult Stem Cells</p>
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			<p class="Authors">&nbsp;</p>
			<p class="Authors"><span class="CharOverride-2">Ahmed Abdelbaset Ismail </span></p>
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			<p class="Affiliations ParaOverride-1">Department of Surgery, Anesthesiology and Radiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Sharkia, Egypt.</p>
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		<div>
			<p class="Abstract ParaOverride-1">&nbsp;</p>
			<p class="Abstract ParaOverride-1"><span class="CharOverride-3">Abstract</span> | The potential application of pluripotent stem cells and retaining their pluripotency without tumour formation in regenerative medicine is very beneficial and challenging. It is really imperative to capture which environmental niche keys make these cells steadily growing and retaining their self-renewal capacity, particularly post–implantation. Based on the results extracted from our and other studies, high mobility group proteins-A (hmga<span class="CharOverride-4">)</span>, particularly hmga2, could fulfil that function very properly through suppression of cell proliferation inhibitors and maintaining/enhancing the genes responsible for stem cell pluripotency such as lin28, klf4, sox2, cmyc, oct4, rex1, sall4, smad3/4, goosecoid (gsc), brachury, nanog and utf1. Based on these observations, we provide evidence that hmga2 protein is an appealing candidate that could be employed in stem cell translational regenerative medicine to achieve that notion. This review states brief background of hmga pathway function with spotlight on the pre-clinical literature that links hmga signaling to adult stem cells proliferation and self-renewal.</p>
		  <p class="Abstract ParaOverride-1">&nbsp;</p>
			<p class="Abstract ParaOverride-1"><span class="CharOverride-3">Keywords </span>| Self-renewal, Pluripotency, Stem cells, hmga, Proliferation</p>
		  <p class="Abstract ParaOverride-1">&nbsp;</p>
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			<p class="Editor----Citation"><span class="CharOverride-3">Editor</span> | Kuldeep Dhama, Indian Veterinary Research Institute, Uttar Pradesh, India.</p>
			<p class="Editor----Citation"><span class="CharOverride-3">Received</span> | March 17, 2015; <span class="CharOverride-3">Revised</span> | March 29, 2015; <span class="CharOverride-3">Accepted </span>| March 30, 2015; <span class="CharOverride-3">Published</span> | April 08, 2015&#9;&#9;</p>
			<p class="Editor----Citation"><span class="CharOverride-3">*Correspondence</span> | Ahmed Abdelbaset Ismail, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Sharkia, Egypt; <span class="CharOverride-3">Email: </span>a4ismail@yahoo.co.uk</p>
			<p class="Editor----Citation"><span class="CharOverride-3">Citation</span> | Ismail AA (2015). Concise review: appreciated signaling role of high mobility group–a proteins for regulation of proliferation, pluripotency and self-renewal of adult stem cells. Adv. Anim. Vet. Sci. 3(5): 276-282.  </p>
			<p class="Editor----Citation"><span class="CharOverride-3">DOI </span>| <a href="http://dx.doi.org/10.14737/journal.aavs/2015/3.5.276.282"><span class="Hyperlink">http://dx.doi.org/10.14737/journal.aavs/2015/3.5.276.282</span></a></p>
			<p class="Editor----Citation"><span class="Editor---Citation CharOverride-3">ISSN (Online)</span> | 2307-8316; <span class="Editor---Citation CharOverride-3">ISSN (Print)</span> | 2309-3331</p>
			<p class="Editor----Citation"><span class="CharOverride-3">Copyright</span> © 2015 Ismail. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</p>
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			<p class="Heading-1--Introduction----">&nbsp;</p>
		  <p class="Heading-1--Introduction----">INTRODUCTION</p>
			<p class="Caps-on-First-Para ParaOverride-1">&nbsp;</p>
			<p class="Caps-on-First-Para ParaOverride-1"><span class="_idGenDropcap-1">S</span>tem cells were primarily studied by Becker’s group, when they observed development of splenic nodules after inoculation of bone marrow mononuclear cells into irradiated mice. The number of these formed nodules was in proportion to the number of injected cells. Analysis of those cells afterwards revealed that those cells have the capacity of self-renewal and potentiality to give rise to several specialized cell types (<a href="#Becker-J--Mc-E--Till-E--1963"><span class="Hyperlink">Becker et al., 1963</span></a>).</p>
		  <p class="Caps-on-First-Para ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Therefore, the capability of self-renewal, repopulation to other stem cells and progenitors, and to giving rise to various committed cell lineages under special conditions are by definition the three essential properties of stem cells. </p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text">Stem cells can generally be categorized into two main types, embryonic and non-embryonic. Embryonic stem cells (ESCs) are derived from blastocyst and have the features of totipotency, thus could progenerate into all cells of embryonic germ layers, while non-embryonic stem cells (non-ESCs), also termed adult stem cells, are multipotent and could propagate into several kinds of tissue committed cells, however this appears to be more finite (<a href="#Lee-H--Hui-J--2006-."><span class="Hyperlink">Lee and Hui, 2006</span></a>). </p>
		  <p class="Body-Text">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Recent perception proposed that the adult tissues contain primitive pluripotent stem cells (<a href="#Kucia-M--Zuba-Surma-K--Wysoczynski-M--Wu-W--Ratajczak-J--Machalinski-B--Ratajczak-M--2007-"><span class="Hyperlink">Kucia et al., 2007</span></a>; <a href="#Santourlidis-S--Wernet-P--Ghanjati-F--Graffmann-N-2011"><span class="Hyperlink">Santourlidis et al., 2011</span></a>; <a href="#Roger-M--Clavreul-A--Huynh-N--Passirani-C--Schiller-P--Vessieres-A--Montero-Menei-C--Menei-P--2012-."><span class="Hyperlink">Roger et al., 2012</span></a>; <a href="#Ogura-F--Wakao-S--Kuroda-Y--Tsuchiyama-K--Bagheri-M--Heneidi-S--Chazenbalk-G--Aiba-S--Dezawa-M--2014"><span class="Hyperlink">Ogura et al., 2014</span></a>). The employment of these recent identified adult pluripotent stem cells potentially for organs regeneration needs to address the biological keys [i.e., high mobility group proteins–A (hmga)], that play a crucial role in maintaining the self-renewal and pluripotency features of these cells especially after theirimplantation (<a href="#Ismail-Ahmed-A--Wagner-S--Murua-Escobar-H--Willenbrock-2012"><span class="Hyperlink">Ismail et al., 2012</span></a>). </p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">In this review we give a brief outlook on stem cells types and stem cell niche with focusing on hmga proteins.</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Heading-1--Introduction----">STEM CELL NICHE </p>
		  <p class="Heading-1--Introduction----">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">A niche or stem cell microenvironment is composed of signaling molecules, cell–cell interaction and neighbouring extracellular matrix (ECM). This three structured dimensional niche so far is considered in jurisdiction of stem cells genes and hence disciplines their stemness properties, e.g., proliferation, self-renewal, migration, homing and commitment to other cell types (<a href="#Watt-F--Hogan-B--2000-"><span class="Hyperlink">Watt and Hogan, 2000</span></a>). </p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">At special circumstances, single signalling pathway generated from this niche is appropriate for enhancing the self-renewal capacity. For instance, in germ line stem cells (GSCs) derived from the Drosophila female, bone morphogenetic protein (bmp) is sufficient for their self-renewal (Xie, 2013), and Notch for C. elegans GSC self-renewal (Byrd and Kimble, 2009). Moreover, activation of Notch1 leads to increasing the haematopoietic stem cells (HSC) self-renewal capacity (<a href="#Kunisato-A--Chiba-S--Nakagami-Yamaguchi-E--Kumano-2003"><span class="Hyperlink">Kunisato et al., 2003</span></a>).</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">On the other hand, most stem cell types are simultaneously activated by several pathways for maintaining long term stem cell self-renewal, e.g., sonic hedgehog (Shh), fibroblast growth factor (FGF) and brain-derived neurotropic factor (BDNF) signalling pathways are essential for neural stem cells (NSC) (<a href="#Zhao-C--Deng-W--Gage-F--2008"><span class="Hyperlink">Zhao et al., 2008</span></a>). Furthermore, there are many cell surface molecules having a critical role in either cell – cell or cell – ECM adhesion in addition to self–renewal of stem cells. From these molecules, cadherin and integrin (<span class="CharOverride-8">α, β</span>) molecules which are observed expressed in a large scale of adult stem cells (<a href="#Chen-S--Lewallen-M--Xie-T--2013-."><span class="Hyperlink">Chen et al., 2013</span></a>).</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Heading-1--Introduction----">PLURIPOTENT STEM CELL TYPES</p>
		  <p class="Heading-1--Introduction----">&nbsp;</p>
			<p class="Heading-2--History-in-MM-">Pluripotent Embryonic Derived Stem Cells </p>
			<p class="Body-Text ParaOverride-1">During the earliest period of embryo formation, the inner cell mass (ICM) of blastocyst “origin of embryonic stem (ES) cells” evolves into two separate germ cell layers, epiblast and hypoblast. The hypoblast cells are responsible for formation of yolk sac “origin of the primitive hemangioblasts”, and the epiblast forms embryonic tissue layers, i.e. ectoderm, mesoderm and endoderm (<a href="#Martin-R--1981"><span class="Hyperlink">Martin, 1981</span></a>). Consequently, Thomson’ group succeeded to isolate these cells and approved the first human ES cell line in 1998 (<a href="#Thomson--J--Itskovitz-Eldor-J--Shapiro-S--Waknitz-M--Swiergiel-J--Marshall-V--Jones-J--1998"><span class="Hyperlink">Thomson et al., 1998</span></a>). However, there are many concerns regarding the use of either ES cells or induced pluripotent stem (iPS) cells such as teratomas formation as result of their unlimited proliferation, genetic manipulation, high rates of immunorejection, and ethical concerns (<a href="#Przyborski-S--2005-.-D"><span class="Hyperlink">Przyborski, 2005</span></a>). </p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Heading-2--History-in-MM-">Non-embryonic Pluripotent Stem Cells </p>
			<p class="Body-Text ParaOverride-1">Mesenchymal stem cells, especially which isolated from adipose tissue, adipose mesenchymal stem cells (ASCs) showed very promising results and considered as alternative multipotent stem cell source to mesenchymal stem cells isolated from bone marrow (BM–MSCs) (<a href="#Zuk-P--Zhu-M--Mizuno-H--Huang-J--Futrell-J--Katz-A--Benhaim-P--Lorenz-H--Hedrick-M--2001"><span class="Hyperlink">Zuk et al., 2001</span></a>).</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Similar to BM–MSCs, ASCs have previously been confirmed for the capability of multilineage differentiation; e.g., a chondrogenic (<a href="#Neupane-M--Chang-C--Kiupel-M--Yuzbasiyan-Gurkan-V--2008"><span class="Hyperlink">Neupane et al., 2008</span></a>; <a href="#Zuk-P--Zhu-M--Mizuno-H--Huang-J--Futrell-J--Katz-A--Benhaim-P--Lorenz-H--Hedrick-M--2001"><span class="Hyperlink">Zuk et al., 2001</span></a>), osteogenic (<a href="#Lo-D--Hyun-J--Chung-M--Montoro-D--Zimmermann-A--Grova-M--Lee-M--Wan-C--Longaker-M--2012"><span class="Hyperlink">Lo et al., 2012</span></a>; <a href="#Levi-B--James-A--Nelson-E--Vistnes-D--Wu-B--Lee-M--Gupta-A--Longaker-M--2010-"><span class="Hyperlink">Levi et al., 2010</span></a>), adipogenic (<a href="#Neupane-M--Chang-C--Kiupel-M--Yuzbasiyan-Gurkan-V--2008"><span class="Hyperlink">Neupane et al., 2008</span></a>; <a href="#Zuk-P--Zhu-M--Mizuno-H--Huang-J--Futrell-J--Katz-A--Benhaim-P--Lorenz-H--Hedrick-M--2001"><span class="Hyperlink">Zuk et al., 2001</span></a>), neurogenic (<a href="#Lin-Y--Chen-X--Yan-Z--Liu-L--Tang-W--Zheng-X--Li-Z--Qiao-J--Li-S.-Tian-W--2006"><span class="Hyperlink">Lin et al., 2006</span></a>; <a href="#Safford-M--Hicok-K--Safford-D--Halvorsen-Y--Wilkison-W--Gimble-J--Rice-H--2002"><span class="Hyperlink">Safford et al., 2002</span></a>), myogenic (<a href="#Wang-X--Zhang-H--Nie-L--Xu-L--Chen-M--Ding-Z--2014-."><span class="Hyperlink">Wang et al., 2014</span></a>; <a href="#Chen-P--Chen-Z--Lin-F--Tian-D--Tang-C--Li-W--2004"><span class="Hyperlink">Chen et al., 2004</span></a>), angiogenic (<a href="#Tang-L--Zhao-Q--Zhang-Y--Cheng-L--Liu-M--Shi-J--Yang-Y--Pan-C--Ge-J--Phillips-M.--2004"><span class="Hyperlink">Tang et al., 2004</span></a>), and cardiomyogenic (<a href="#Gwak--J--Bhang-H--Yang-S--Kim-S--H--Lee-H--Kim-S--2009-."><span class="Hyperlink">Gwak et al., 2009</span></a>) lineages. </p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">There are however some specific advantageous criteria make the use of ASCs as rich sources for adult stem cells very appealing. Obtaining sufficient amount of adipose tissue samples using lowest levels of invasion and pain in addition to high capability of ASCs to retain their multipotency and phenotype after long term of culturing reach to 25 passages make these cells very attractive (<a href="#Liu-T--Martina-M--Hutmacher-D--Hui-J--Lee-H--Lim-B--2007-."><span class="Hyperlink">Liu et al., 2007</span></a>; <a href="#Zhu-Y--Liu-T--Song-K--Fan-X--Ma-X--Cui-Z--2008"><span class="Hyperlink">Zhu et al., 2008</span></a>).</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Following, recent pluripotent stem cell populations have been identified and raised the consideration of the scientific community as a valuable alternative candidate to the argumentative ES cells and genetically reprogrammed iPS cells. From these cells, multipotent adult progenitor cells (MAPCs) (<a href="#Jiang-Y--Jahagirdar-N--Reinhardt-L--Schwartz-E--Keene-2002"><span class="Hyperlink">Jiang et al., 2002</span></a>), human marrow-isolated adult multilineage inducible (MIAMI) cells, unrestricted somatic stem cells (USSCs), very small embryonic-like stem cells (VSELs), stimulus-triggered acquisition of pluripotency (STAP), and  multilineage differentiating stress enduring (Muse) cells are well known. MAPCs isolated from bone marrow, have been shown to regenerate the infarcted myocardium in mouse model (<a href="#Dimomeletis-I--Deindl-E--Zaruba-M--Groebner-2010"><span class="Hyperlink">Dimomeletis et al., 2010</span></a>). VSELs, MIAMI and USSCs were isolated from bone marrow and cord blood and showed pluripotency and non tumorgenic properties (<a href="#Kucia-M--Zuba-Surma-K--Wysoczynski-M--Wu-W--Ratajczak-J--Machalinski-B--Ratajczak-M--2007-"><span class="Hyperlink">Kucia et al., 2007</span></a>; <a href="#Santourlidis-S--Wernet-P--Ghanjati-F--Graffmann-N-2011"><span class="Hyperlink">Santourlidis et al., 2011</span></a>; <a href="#Roger-M--Clavreul-A--Huynh-N--Passirani-C--Schiller-P--Vessieres-A--Montero-Menei-C--Menei-P--2012-."><span class="Hyperlink">Roger et al., 2012</span></a>). </p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">In addition to other regenerative capacities of VSEL <span class="CharOverride-4">in vivo</span>, more recent published paper has showed very promising neovasculogenic capacity of VSELs in patients suffering from critical limb ischemia (<a href="#Guerin-L--Loyer-X--Vilar-J--Cras-A--Mirault-T--Gaussem-P--Silvestre-S.-Smadja-M--2015"><span class="Hyperlink">Guerin et al., 2015</span></a>). </p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">In 2010, <span class="CharOverride-4">Muse cells</span> have been identified from adherent mesenchymal stromal cells isolated from bone marrow and lipoaspirats and also from commercially available human adipose stem cells (<span class="CharOverride-4">Muse–AT cells</span>). This population of cells showed expression of pluripotency marker stage-specific embryonic antigen-3 (ssea-3) as well as the double expression of mesenchymal cell specific markers CD105 and CD90. However, as declared by Simerman et al. and others, <span class="CharOverride-4">Muse cells</span> displayed only a slight increase in expression of pluripotency markers (sox2, naong, oct4) when compared with non-Muse cells (<a href="#Kuroda-Y--Kitada-M--Wakao-S--Nishikawa-K--Tanimura-2010"><span class="Hyperlink">Kuroda et al., 2010</span></a>; <a href="#Wakao-S--Kitada-M--Kuroda-Y--Shigemoto-T--Matsuse-D-2011"><span class="Hyperlink">Wakao et al., 2011</span></a>; <a href="#Ogura-F--Wakao-S--Kuroda-Y--Tsuchiyama-K--Bagheri-M--Heneidi-S--Chazenbalk-G--Aiba-S--Dezawa-M--2014"><span class="Hyperlink">Ogura et al., 2014</span></a>; <a href="#Simerman-A--Dumesic-D--Chazenbalk-G--2014"><span class="Hyperlink">Simerman et al., 2014</span></a>).</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Heading-1--Introduction---- ParaOverride-1">LINK BETWEEN HMGA AND ADULT STEM CELLS SELF-RENEWAL</p>
		  <p class="Heading-1--Introduction---- ParaOverride-1">&nbsp;</p>
			<p class="Heading-2--History-in-MM-">Pluripotency Gene Expression </p>
			<p class="Body-Text ParaOverride-1">Pluripotency means the tremendous capacity of stem cells to differentiate into all types of cells specified from all embryonic germ layers. Studies of the relationship between pluripotency and gene expression led to the identification of variety of markers specific for pluripotent stem cells in mammals. These transcription factors including oct3/4 (<a href="#Rizzino-A--2009-.-Sox2"><span class="Hyperlink">Rizzino, 2009</span></a>), sox2, nanog (<a href="#Mitsui-K--Tokuzawa-Y--Itoh-H--Segawa-K--Murakami-M--2003"><span class="Hyperlink">Mitsui et al., 2003</span></a>), cmyc (<a href="#Smith-K--Singh-A--Dalton-S--2010"><span class="Hyperlink">Smith et al., 2010</span></a>), rex-1 (<a href="#Ben-Shushan-E--Thompson-R--Gudas-J--Bergman-Y--1998"><span class="Hyperlink">Ben-Shushan et al., 1998</span></a>), tra-1 (<a href="#Andrews-W--Banting-G--Damjanov-I--Arnaud-D--Avner-P--1984"><span class="Hyperlink">Andrews et al., 1984</span></a>) and klf4 (<a href="#Chan-K--Zhang-J--Chia-Y--Chan-S--Sim-S--Tan-S--Oh-K--Ng-H--Choo-B--2009"><span class="Hyperlink">Chan et al., 2009</span></a>), have been shown to contribute to the long-term maintenance of an embryonic stem (ES) cell-like phenotype, proliferation and maintenance as well as self-renewal of pluripotent cells. Currently, ssea–3 and –4 are commonly used as surface markers to prove the pluripotency of human stem cells (<a href="#Yang-Z--Liu-J--Liu-H--Qiu-M--Liu-Q--Zheng-L--Pang-M--Quan-F--Zhang-Y--2013b"><span class="Hyperlink">Yang et al., 2013b</span></a>; <a href="#Tsai-T--Lee-H--Chang-S--Wang-C--Tu-Y--Lin-Y--Hwang-D--Wu-C--Wong-C--2013"><span class="Hyperlink">Tsai et al., 2013</span></a>; <a href="#Bouwens-L--2012"><span class="Hyperlink">Bouwens, 2012</span></a>; <a href="#Yang-J--Mumaw-J--Liu-Y--Stice-S--West-F--2013a"><span class="Hyperlink">Yang et al., 2013a</span></a>; <a href="#Truong-T--Huynh-K--Nakatsu-M--Deng-S--2011"><span class="Hyperlink">Truong et al., 2011</span></a>; <a href="#Holford-C--Case-P--Lawson-N--1994-"><span class="Hyperlink">Holford et al., 1994</span></a>). Ssea-3 and ssea-4 are globoseries glycosphingolipid surface epitopes and their expression indicates that the ES cells have increased the levels of a metabolic activity, especially during early embryogenesis (<a href="#Suila-H--Pitkanen-V--Hirvonen-T--Heiskanen-A--Anderson-2011"><span class="Hyperlink">Suila et al., 2011</span></a>).</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">The concept of retaining the pluripotency and self–renewal potentiality of stem cells, especially post transplantation <span class="CharOverride-4">in vivo</span> is really critical. For this reason, the characterization of signaling molecules governing that notion of regular proliferation and self-renewal in steady states is really essential for both <span class="CharOverride-4">in vitro</span> and <span class="CharOverride-4">in vivo</span> studies. Some recent studies have focused on that subject and based on their <span class="CharOverride-4">in vitro</span> and <span class="CharOverride-4">in vivo</span> data, they proposed that “hmga” can influence and actively regulate these actions (<a href="#Nishino-J--Kim-S--Zhu-Y--Zhu-H--Morrison-S--2013-.-A-n"><span class="Hyperlink">Nishino et al., 2013</span></a>; <a href="#Ismail-Ahmed-A--Wagner-S--Murua-Escobar-H--Willenbrock-2012"><span class="Hyperlink">Ismail et al., 2012</span></a>; <a href="#Monzen-K--Ito-Y--Naito-A--Kasai-H--Hiroi-Y--Hayashi-D--2008"><span class="Hyperlink">Monzen et al., 2008</span></a>; <a href="#Nishino-J--Kim-I--Chada-K--Morrison-S--2008-."><span class="Hyperlink">Nishino et al., 2008</span></a>; <a href="#Sanna--S--Jackson-A--Nagaraja-R--Willer-C--Chen-W--Bonnycastle-2008"><span class="Hyperlink">Sanna et al., 2008</span></a>).</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Heading-2--History-in-MM-">High Mobility Group–A (HMGA) Proteins </p>
			<p class="Body-Text ParaOverride-1">Hmga proteins (formerly known as HMGI/Y) are category of large unique nuclear non-histone chromosomal architectural proteins (<a href="#Grosschedl-R--Giese-K--Pagel-J--1994"><span class="Hyperlink">Grosschedl et al., 1994</span></a>). AT–rich DNA nucleotide sequences with acidic C-terminus (<a href="#Reeves-R--2000-."><span class="Hyperlink">Reeves, 2000</span></a>) are the common structural and active motifs in encoded genes of those proteins. This type of unique proteins is specialized into two distinguished encoded genes, hmga1 and hmga2 (<a href="#Friedmann-M--Holth-T--Zoghbi-Y--Reeves-R--1993"><span class="Hyperlink">Friedmann et al., 1993</span></a>; <a href="#Johnson-R--Lehn-A--Reeves-R--1989-."><span class="Hyperlink">Johnson et al., 1989</span></a>). </p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Heading-2--History-in-MM-">Importance of HMGA Proteins Expression</p>
			<p class="Body-Text ParaOverride-1">Initially, has been approved that hmga1 is important for cell differentiation, while hmga2 is commonly involved during stem cells proliferation and self–renewal (<a href="#Vartiainen-E--Palvimo-J--Mahonen-A--Linnala-Kankkunen-A--Maenpaa-P--1988"><span class="Hyperlink">Vartiainen et al., 1988</span></a>). </p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">These data <span lang="en-US">were afterwards confirmed by another group</span> who declared that up regulation of these unique proteins in unspecialized and primitive stem cells isolated from embryos revealed the crucial role of hmga proteins in management of stem cell differentiation and proliferation. Furthermore, it has been ascertained that hmga2 is expressed by embryonic stem cells isolated from either murine or human blastocyst (<a href="#Tay-Y--Peter-S--Rigoutsos-I--Barahona-P--Ahmed-S--Droge-P--2009-"><span class="Hyperlink">Tay et al., 2009</span></a>). All these data provide evidence of the very crucial role of hmga protein during embryonic and foetal growth and development.</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Heading-2--History-in-MM-">HMGA Proteins and Pluripotency Genes </p>
			<p class="Body-Text">The pathways link hmga2 to other some cellular genes that control self–renewal, proliferation and pluripotency are displayed in <a href="#Figure-1-"><span class="Hyperlink">Figure 1</span></a>. Expression experiments performed on human ES cells at mRNA levels indicated that there is a clear correlation between the expression level of hmga2 and pluripotency genes including utf1, sox2 and oct4 (<a href="#Li-O--Li-J--Droge-P--2007"><span class="Hyperlink">Li et al., 2007</span></a>). </p>
		  <p class="Body-Text">&nbsp;</p>
			
            <div class="pt" > <a href="http://nexusacademicpublishers.com/uploads/figures/20150409144243.png" target="new"><img class="img_display" src="http://nexusacademicpublishers.com/uploads/figures/20150409144243.png" width="80" height="80"></a>
            
            <p class="Figure--and-Table-Heading ParaOverride-1"><span class="CharOverride-3"><a id="Figure-1-"></a>Figure 1: </span><a href="http://nexusacademicpublishers.com/uploads/figures/20150409144243.png">Hmga2 regulates stem cell proliferation and pluripotency</a></p>
       </div>

		  <p class="Figure--and-Table-Heading ParaOverride-1"><span class="CharOverride-5">Hmga2 controls the regulation of cell growth inhibitors (P16, P19) and accordingly maintains or accelerates the proliferation of stem cells. On the other side hmga2 plays a crucial role in up regulation of pluripotency specific genes hence retains the pluripotency features of stem cells.</span></p>
		  <p class="Figure--and-Table-Heading ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Further, hmga2 were down–regulated through let-7 microRNAs up-regulation pathway after inducing germline derived cancer cell line e.g., murine<span class="CharOverride-4"> </span>P19 teratocarcinoma cell line toward neuronal lineage (<a href="#Eda-A--Tamura-Y--Yoshida-M--Hohjoh-H--2009"><span class="Hyperlink">Eda et al., 2009</span></a>). </p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Similarly, down regulation of proliferation inhibitors including let-7b, p19 (arf) and p16 (ink4a) mediated by hmga2 expression led to maintenance of mouse neural stem cells phenotype <span class="CharOverride-4">in vitro</span> (<a href="#Nishino-J--Kim-I--Chada-K--Morrison-S--2008-."><span class="Hyperlink">Nishino et al., 2008</span></a>). Other results indicated the suppressing effect of down regulated cmyc and hmga1<span class="CharOverride-4"> </span>expression on proliferation of stomach cancer cell line through <span class="CharOverride-4">wnt3a/beta-catenin </span>signaling pathway (<a href="#Akaboshi-S--Watanabe-S--Hino-Y--Sekita-2009"><span class="Hyperlink">Akaboshi et al., 2009</span></a>). </p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Furthermore, at a molecular level, our previous study has demonstrated that relative expression of pluripoteny specific genes hmga2, oct4, klf4, sox2 and cmyc<span class="CharOverride-4"> </span>were maintained after <span class="CharOverride-4">in vitro</span> stimulation of canine adipose mesenchymal stem cells (cASCs) with recombinant human hmga2 protein (<a href="#Ismail-Ahmed-A--Wagner-S--Murua-Escobar-H--Willenbrock-2012"><span class="Hyperlink">Ismail et al., 2012</span></a>) as depicted in<span class="CharOverride-3"> </span><a href="#Figure-2"><span class="Hyperlink">Figure 2</span></a>.</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			
             <div class="pt" > <a href="http://nexusacademicpublishers.com/uploads/figures/20150409140345.png" target="new"><img class="img_display" src="http://nexusacademicpublishers.com/uploads/figures/20150409140345.png" width="80" height="80"></a>
            
            <p class="Figure--and-Table-Heading ParaOverride-1"><span class="CharOverride-3"><a id="Figure-2"></a>Figure 2: </span><a href="http://nexusacademicpublishers.com/uploads/figures/20150409140345.png">Relative pluripotency genes expression by stimulated and unstimulated canine adipose mesenchymal stem cells (cASCs) with hmga2 protein (50, 100 ng/ml) after real time PCR</a></p>
       </div>
			
		  <p class="Figure--and-Table-Heading ParaOverride-1"><span class="CharOverride-5">OCT4, KLF4, cMYC, HMGA2 and SOX2 are expressed by cASCs but no difference was detected at the used concentrations.</span></p>
			<p class="Heading-2--History-in-MM-">&nbsp;</p>
		  <p class="Heading-2--History-in-MM-">Role of HMGA Proteins in Cell Proliferation </p>
			<p class="Body-Text ParaOverride-1">The role of hmga proteins on proliferation of undifferentiated ES cells and tissue specified cells have been proposed by several studies (<a href="#Pierantoni-G--Battista-S--Pentimalli-F--Fedele-M--Visone-R--Federico-A--Santoro-M--Viglietto-G--Fusc"><span class="Hyperlink">Pierantoni et al., 2003</span></a>; <a href="#Caron-L--Bost-F--Prot-M--Hofman-P--Binetruy-B--2005-"><span class="Hyperlink">Caron et al., 2005</span></a>; <a href="#Li-O--Li-J--Droge-P--2007"><span class="Hyperlink">Li et al., 2007</span></a>; <a href="#Richter-A--Hauschild-G--Murua-Escobar-H--Nolte-I--Bullerdiek-J--2009"><span class="Hyperlink">Richter et al., 2009</span></a>; <a href="#Ismail-Ahmed-A--Wagner-S--Murua-Escobar-H--Willenbrock-2012"><span class="Hyperlink">Ismail et al., 2012</span></a>). The action of hmga1 protein has been assessed for accelerating enhanced adipocyte proliferation and expansion of human fat derived tumours (<a href="#Pierantoni-G--Battista-S--Pentimalli-F--Fedele-M--Visone-R--Federico-A--Santoro-M--Viglietto-G--Fusc"><span class="Hyperlink">Pierantoni et al., 2003</span></a>). It has also been demonstrated the critical regulatory function of hmga2 in skeletal muscles formation from murine ES cells (<a href="#Caron-L--Bost-F--Prot-M--Hofman-P--Binetruy-B--2005-"><span class="Hyperlink">Caron et al., 2005</span></a>) and adipogenic lineage differentiation of MSCs (<a href="#Li-O--Li-J--Droge-P--2007"><span class="Hyperlink">Li et al., 2007</span></a>). Additionally, porcine chondrocytes showed significant increased proliferation <span class="CharOverride-4">in vitro</span>, when incubated with hmga1 and hmga2 in different supra–physiological concentrations (<a href="#Richter-A--Hauschild-G--Murua-Escobar-H--Nolte-I--Bullerdiek-J--2009"><span class="Hyperlink">Richter et al., 2009</span></a>). In consistently, hmga1 significantly did reduce cASCs proliferation, when employed alone or in combination with hmga2, however there was no enhanced or inhibiting effect observed after cultivation of cASCs with hmga2 protein <span class="CharOverride-4">in vitro</span> (<a href="#Figure-3-"><span class="Hyperlink">Figure 3</span></a>) (<a href="#Ismail-Ahmed-A--Wagner-S--Murua-Escobar-H--Willenbrock-2012"><span class="Hyperlink">Ismail et al., 2012</span></a>). More recent study revealed that lin28b with hmga2 may act as a regulator of HSC self-renewal potential (<a href="#Copley-R--Babovic-S--Benz-C--Knapp-J--Beer-A--Kent-G--2013"><span class="Hyperlink">Copley et al., 2013</span></a>). Furthermore, a <span class="highlight">network</span> of <span class="highlight">hetero-chronic</span> gene products <span class="highlight">including</span> lin28a, let-7, <span class="highlight">imp1</span>, and hmga2 have a vital role in regulation of neural <span class="highlight">stem</span> <span class="highlight">cell</span> <span class="highlight">characteristics. </span></p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			
            <div class="pt" > <a href="http://nexusacademicpublishers.com/uploads/figures/20150409142146.png" target="new"><img class="img_display" src="http://nexusacademicpublishers.com/uploads/figures/20150409142146.png" width="80" height="80"></a>
            
          <p class="Figure--and-Table-Heading ParaOverride-1"><span class="CharOverride-3"><a id="Figure-3-"></a>Figure 3: </span><a href="http://nexusacademicpublishers.com/uploads/figures/20150409142146.png">Proliferation assay of stimulated cASCs with hmga proteins</a></p>
       </div>
			
		  <p class="Figure--and-Table-Heading ParaOverride-1"><span class="CharOverride-5">Hmga1 has significant inhibiting effect on cell proliferation when used alone (10–200 ng/ml) or combined with hmga2 (100, 200 ng/ml). Contrarily, there is no significant differences in cell proliferation are observed in hmga2-treated groups compared to un-stimulated cells. One-way analysis of variance and Tukey test was performed for statistical comparison (significance levels: *P&lt;0.05; ** P&lt;0.01; *** P&lt;0.001).</span></p>
		  <p class="Figure--and-Table-Heading ParaOverride-1">&nbsp;</p>
			<p class="Heading-1--Introduction----">CONCLUSION</p>
		  <p class="Heading-1--Introduction----">&nbsp;</p>
			<p class="Body-Text ParaOverride-1">Pluripotency and self-renewal are overwhelmingly considered the most essential properties of adult pluripotent stem cells. These features are regulated by unique stem cell specific transcription factors, namely pluripotency genes. These factors include lin28, klf4, sox2, cmyc, oct4, rex1, sall4, smad3/4, goosecoid (gsc), brachury, nanog and utf1. To retain the self-renewal capacity of either transplanted or cultivated pluripotent stem cells, the balances between these transcription factors and other signaling controlling molecules are fully critical and needed to be elucidated. Thereby, the identification of the biological keys that control that notion is very imperative for both <span class="CharOverride-4">in vitro</span> and <span class="CharOverride-4">in vivo</span> strategies. Recent studies performed by us and others proposed that hmga proteins have the potentiality to govern those functions via direct or indirect regulation of other cellular processes – controlling genes.</p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Heading-1--Introduction----">ACKNOWLEDGEMENTS</p>
		  <p class="Heading-1--Introduction----">&nbsp;</p>
			<p class="Body-Text ParaOverride-1"><span class="Strong CharOverride-12">This work was supported by Faculty of Veterinary Medicine, Zagazig University and Ministry of Higher Education, Egypt.</span></p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
			<p class="Heading-1--Introduction----"><span class="Strong CharOverride-13">CONFLICT OF INTEREST</span></p>
		  <p class="Heading-1--Introduction----">&nbsp;</p>
			<p class="Body-Text ParaOverride-1"><span class="Strong CharOverride-12">There is no conflict of interest</span></p>
		  <p class="Body-Text ParaOverride-1">&nbsp;</p>
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