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Amnion-Derived Stem Cells: in Quest of Clinical Applications

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Amnion-Derived Stem Cells: in Quest of Clinical Applications Miki Stem Cell Research & Therapy 2011, 2:25 http://stemcellres.com/content/2/3/25 REVIEW Amnion-derived stem cells: in quest of clinical applications Toshio Miki*1,2 stem (ES) cells, and induced pluripotent stem (iPS) cells. Abstract Although their biological potentials have been demon- In the promising fi eld of regenerative medicine, human strated, none of these cells is widely accepted as a perinatal stem cells are of great interest as potential defi nitive cell source for clinical applications. Each cell stem cells with clinical applications. Perinatal stem type possesses diff erent advantages as well as limitations cells could be isolated from normally discarded human for their use, such as safety or availability. It will be placentae, which are an ideal cell source in terms of helpful to search for a potential stem cell source from the availability, the fewer number of ethical concerns, perspective of its potential for clinical application. What less DNA damage, and so on. Numerous studies have is the sine qua non of the cells for clinically applicable demonstrated that some of the placenta-derived regenerative medicine? At the end of this review, this cells possess stem cell characteristics like pluripotent question will be discussed further. diff erentiation ability, particularly in amniotic epithelial Th ere is increasing evidence that the human placenta (AE) cells. Term human amniotic epithelium contains contains pluripotent or multipotent stem cells or both. a relatively large number of stem cell marker-positive Various multipotent stem cells have been isolated from cells as an adult stem cell source. In this review, we diff erent parts of the human placenta, such as the introduce a model theory of why so many AE cells amnion, chorion, umbilical cord, and fetal blood. As possess stem cell characteristics. We also describe placenta-derived cells, these stem cells have common previous work concerning the therapeutic applications advantages (Figure 1). Specifi c types of placenta-derived and discuss the pluripotency of the AE cells and stem cells, such as trophoblastic, hematopoietic, and potential pitfalls for amnion-derived stem cell research. mesen chymal stroma cells, have been discussed else- where [1-3]. Here, we will review stem cells derived from the amnion of human placentae, specifi cally amniotic Introduction epithelial (AE) cells. First, we will summarize previous Th e emerging fi eld of regenerative medicine requires a studies that have demonstrated the unique stem cell reliable cell source in addition to biomaterial scaff olds characteristics of AE cells. On the basis of these fi ndings, and cytokine/growth factors. Th e ‘cell’ is a particularly we introduce a model theory that explains why some AE critical element for cell replacement therapies in order to cells, unlike other adult somatic stem cells, may possess provide a safe and suffi cient cell supply for clinical pluripotent features. Second, we will discuss topics and applications. Eff orts to search for an adequate cell type pitfalls that are currently under discussion. Th ird, and cell source have been conducted and have continued previous works that are leading the therapeutic appli- along with the discussions for their use in clinical cation of AE cells will be summarized. Last, the potential application. of the clinical application of AE-derived stem cells and Th ere are many potential cell sources for regenerative the future direction of the research are discussed. medicine, including bone marrow-derived mesenchymal stem cells, tissue-specifi c progenitor cells, embryonic Amniotic epithelial cells: what is so special about them? *Correspondence: [email protected] Th e epithelial cell population could be exclusively iso- 2Department of Biochemistry and Molecular Biology, Eli and Edythe Broad Center lated from the amnions of term human placentae by for Regenerative Medicine and Stem Cell Research at USC University of Southern California, Keck School of Medicine, 1425 San Pablo Street, BCC 312, MC 9080, specifi c enzymatic digestion [4]. Th e cell surface antigen Los Angeles, CA 90089, USA profi le data indicate that AE cells are basically Full list of author information is available at the end of the article homogeneous cell populations for most of the cell surface markers [5]; however, the reactivity against ‘stem cell’- © 2010 BioMed Central Ltd © 2011 BioMed Central Ltd specifi c antigens varies. Following isolation, some of the Miki Stem Cell Research & Therapy 2011, 2:25 Page 2 of 11 http://stemcellres.com/content/2/3/25 Figure 1. Advantages of amniotic epithelial cells for clinical application. Fundamental advantages of placenta-derived stem cells and amniotic epithelial cell-specifi c biological advantages are summarized. QOL, quality of life. AE cells express stem cell surface markers, such as stage- into two layers: the hypoblast and the epiblast. Th e specifi c embryonic antigen-3 (SSEA-3) and SSEA-4 and epiblast is the source of all three germ layers and tumor rejection antigen 1-60 (TRA1-60) and TRA1-81, eventually forms the developing embryo. At the same which are known to be expressed on human ES cells [6]. time, a small cavity (amniotic cavity) appears within the About 15%, 50%, and 5% to 10% of naïve human AE epiblast. Epiblast cells adjacent to the amniotic cavity (hAE) cells are positive for SSEA-3, SSEA-4, and TRA (Figure 2) are called amnioblasts, which eventually form stem cell markers, respectively [7]. Normally, undiff er en- the amniotic epithelium. Concomitantly, some of the tiated stem cells homogeneously express these stem cell migrating hypoblasts transdiff erentiate into mesenchy- markers [6]. Th e variance of the ratio of stem cell marker- mal cells (extraembryonic mesoderm) and develop into positive cells indicates that naïve AE cell populations the amniotic connective tissue. Th e epiblast-amnioblast contain cells in various stage of ‘stemness’. Interestingly, segregation occurs before gastrulation, which is con- the ratios of stem cell marker-positive AE cells (5% to sidered the fi rst dynamic event of organogenesis. All 50%) are considerably higher than for other somatic/ short-range organogenetic signals may not reach the tissue stem cells. Most of the somatic/tissue stem cells segregated stem cells throughout gestation. For instance, are 0.1% to 0.01% of the residing tissue. For instance, the cardiogenesis is a complex event that is orchestrated by hematopoietic stem cell population is only 0.01% to short-range fi broblast growth factors (FGFs) and Hedge- 0.05% of all bone marrow cells [8]. Th e relatively high hog signals [16]. Th erefore, some epiblasts/amnioblasts ratio of stem cell marker-positive cells in AE cell that are spatially segregated by the amniotic cavity from populations as somatic stem cells could be explained by the epicenter of organogenesis may escape from these the model theory. Th e cell surface markers that are diff erentiation cues. After 10 months, although most of expressed by hAE cells are summarized and compared the cells have diff erentiated by following the epithelial with the expression of other types of stem cells in Table 1 cell fate and have lost their stem cell characteristics, [2,7,9-15]. about 5% to 10% of the AE cells may retain the epiblast- like stem cell characteristics at term [7]. If this model Stem cells ‘left behind’: developmental uniqueness theory is correct, fetal amniotic epithelium should con- of the amniotic epithelial cell tain more stem cell marker-positive cells than term Unlike other parts of the placenta, the amniotic epithe- amniotic epithelium. Izumi and colleagues [17] demon- lium is a tissue of epiblastic origin. Human amnioblast is strated that about 40% and 30% of fetal (early second derived from the pluripotent epiblast around the eighth trimester) AE cells are positive for stem cell markers day following fertilization, whereas other parts of the TRA1-60 and TRA 1-81, respectively, whereas 5% of placenta are derived from the trophectoderm. When the term AE cells are positive for these markers. Th e amnion blastocyst is partially embedded in the endometrial is a fairly large tissue that may not be very uniform but is stroma, the inner cell mass (or embryoblast) diff erentiates rather regionalized [18]. To exclude variances due to the Miki Stem Cell Research & Therapy 2011, 2:25 Page 3 of 11 http://stemcellres.com/content/2/3/25 Table 1. Comparison of stem cell surface marker expression in stem cells AE ES NS MS HS First author Fatimah Bilic Stadler Banas Parolini Minas Ilancheran Miki Osman Reference [9] [10] [11] [12] [2] [13] [14] [5,7] [15] c-met + + CCR4 − ± + CD10 + + CD105 Up + + CD106 (VCAM-1) − + CD117 (c-kit) − − ± ± + + CD13 Up + + CD14 − CD133 − − + + + + CD140b + CD166 (ALCAM) + + + CD24 + + + + CD29 + + + + CD31 (PECAM-1) − − − CD324 (E-cadherin) + + + + CD338 (ABCG2) + + + + + CD34 − − − − − − + CD349 − CD44 + + Up + + CD45 − − − − CD49d − CD49e + Up + CD49f + + + CD54 (ICAM-1) + + + CD73 + + + + CD9 + + + + + CD90 + Up Up + + + GCTM2 + + + Sialyl Lewis a + SSEA-1 − − − − − SSEA3 + + + + + + SSEA4 + + + + + + + + TRA1-60 Down + + + + + TRA1-81 Down + + + + + −, negative; +, positive; ±, weak; AE, amniotic epithelial cell; Down, downregulated each antigen expression; ES, embryonic stem cell; HS, hematopoietic stem cell; MS, mesenchymal stem cell; NS, neural stem cell; SSEA, stage-specifi c embryonic antigen; TRA, tumor rejection antigen; Up, upregulated each antigen expression. regionalized stem cell localization, amnion samples were unclear. It has been shown that cultured AE cells secrete harvested from three diff erent parts of the amnion: the various morphogens and growth factors such as epider- center of the disc, the edge of the disc, and the membrane mal growth factor, Noggin, Activin [20], platelet-derived part. Th ere was no signifi cant diff erence between samples growth factor, vascular endothelial growth factor, angio- by region, at least in these three parts [19]. On the other genin, transforming growth factor-beta-2 (TGF-β2), and hand, the mechanism and signals that induce diff eren- tissue inhibitors of metalloproteinases (TIMP-1 and tiation on 90% of amnioblasts of epiblast origin are TIMP-2) [21].
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