Printer Friendly

The Impact of Epigenetic Signatures on Amniotic Fluid Stem Cell Fate.

1. Introduction

One of the fascinating fields of modern medicine is epigenetics, a new discipline that studies heritable changes in gene expression not related to alterations of DNA sequence. The role of epigenetic mechanisms in cell fate determination is widely reported in scientific literature [1-3]. Alterations of the epigenetic networks may lead to the loss of self-renewal capacity and lineage commitment anomalies resulting in dysregulation of the differentiation process of intermediate progenitors [4-6]. The full complexity of epigenetic machinery is only partially known, and the major molecules involved in regulating gene expressions (DNA methylation, histone modifications, and small noncoding RNAs) can contribute to cellular plasticity and influence the transition from a pluripotent state to a multipotent state, in the context of landscape models [7, 8]. During the differentiation process, DNA methylation plays an important role in silencing pluripotency-related genes and activating tissue-specific genes, thus producing a cellular memory that defines the cell fate commitment. Recent findings have shown that gene regulation at posttranscriptional levels influences the stemness and biologic characteristics of stem cells [9-11]. Current studies on miRNAs have revealed a signature that is characteristic for the state of embryonic stem cells (ESCs) [12-14]. Indeed, some miRNA clusters act as cell cycle moderators increasing ESC proliferation due to the promoted transition from the G phase to S1 phase [15]. Moreover, miR-291-3p, miR-294, and miR-295 families regulate core pluripotency transcription factors (Oct4, Nanog, and Sox2) and promote somatic reprogramming through signaling cascades as mesenchymal-to-epithelial changes necessary for colony formation, a reduction of differentiation potential, and an inhibition of cellular senescence [16]. Another significant epigenetic process is dynamic chromatin remodeling associated with cell fate decisions. The advent of high-throughput next-generation sequencing (NGS) has increased new insights regarding the function and activity of histones. For instance, acetylation of histone residues generally is associated with gene activation, while methylation can have both activating and repressive roles [17]. Although every stem cell has a unique epigenetic signature, a common message derives from all these studies: cells need both the DNA "hardware" and the epigenetic "software" in order to respond to the requirement of the tissues [18]. A better understanding of all these complicated processes is necessary to choose a safe source of stem cells to be used in the clinical context. In view of this evidence, AFSCs represent a novel and alternative resource for regenerative medicine, due to their high renewal capacity and the plasticity intermediate between embryonic and adult stem cell types [19-21]. These cells are obtained during the process of amniocentesis (around the 16th week of pregnancy) and contain a heterogeneous population of cell types originating from embryonic and extraembryonic tissues. For this reason, they could provide an in vitro model for studying epigenetic regulation in early human development. A growing body of evidence has demonstrated that the ability of differentiation of AFSCs [22-24] is the result of a complex and dynamic network of transcriptional factors, and certainly the epigenetic mechanisms play a central role in activation and/or repression of tissue-specific genes (see Figure 1). To date, how these cells acquire new fates is still unknown and many processes governing their biology should be explored in order to add new knowledge to this complicated epigenetic puzzle. This review summarizes recent findings on epigenetic signatures of AFSCs related to lineage commitment and plasticity, highlighting their potential into clinical practice.

2. Epigenetic Changes in AFSC Reprogramming

In recent years, AFSCs have emerged as an alternative source for cell reprogramming and regenerative medicine since they display an "intermediate phenotype" between embryonic and adult stem cells, in addition to an active telomerase activity and a high degree of plasticity [23, 24]. They are easily achievable, show high proliferation rate and negligible immunogenicity, lack tumorigenicity, and demonstrate no ethical concerns [25]. The identification of the "best" cell type and the right protocol that guarantee the maximum efficiency during the generation of induced pluripotent stem cells (iPSCs) represents an important milestone in the knowledge of human diseases. In iPSCs, epigenetic modifications cause the change in the expression of many genes, suggesting that such modifications may directly determine the fate of the stem cells [26]. In light of these considerations, several studies have documented the capacity of human amniotic fluid stem cells (hAFSCs) to generate iPSCs using defined protocols. The application of hAFSCs in the reprogramming process has been pioneered by Li and colleagues in 2009 when they demonstrated for the first time an efficient generation of human amniotic fluid-derived induced pluripotent stem cells (hAFiPSCs). In this study, the pluripotency was induced through retroviral delivery of four human transcription factors (Oct4/Sox2/KLF4/c-Myc) and all three germ layers are found in embryoid bodies and teratomas, respectively [27]. More detailed molecular studies demonstrated the ability of hAFiPSCs to differentiate into the extraembryonic trophoblast lineage, and comparative transcriptome analysis with human embryonic stem cell (hESC) lines revealed a subset of genes expressed in all pluripotent cell lines including common self-renewal and pluripotency-associated gene regulatory network upon cellular reprogramming [28, 29]. For this reason, AFSCs could be easier than somatic cells to reprogram to pluripotency because of their similarity in transcriptional and epigenetic states with embryonic cell types. Pluripotent stem cells are characterized by a unique epigenetic profile enhanced for active chromatin modifications, histone acetylation, and hypomethylated DNA [30]. In particular, the initial phase of reprogramming is strictly related to an open chromatin state and active transcription, such as acetylation of histones H3 and H4 [31]. Similarly, trimethylation of the histone 3 at the fourth lysine residue (H3K4me3) is considered as a potent marker of active chromatin state [32] and is associated with DNA hypomethylation in many genomic loci in iPSCs [31, 33, 34]. Despite the presence of the activating histone marks, H3K9 methylation is considered as a repressive marker and during reprogramming it is necessary to repress H3K9 methyltransferases (Ehmt2, Setdb1, and Suv39h1/2) in order to open the chromatin [35-37]. Generally, modifications like methylation at of H3K9 and H3K27 residues are associated with compact chromatin and transcriptional repression, often found in silent gene loci (see Figure 2) [38].

Although the generation of a nonviral iPSC remains an important challenge, it has been reported for the first time that human first-trimester AFSCs can be fully reprogrammed to pluripotency without ectopic factors, by culture on Matrigel in a hESC medium supplemented with the histone deacetylase inhibitor (HDACi) valproic acid (VPA) [39]. These data identify an ideal human cell source for rapid and efficient generation of iPSCs and the possibility to study in vitro genetic disorders associated with pregnancy. In fact, AFSCs can be used to generate patient-specific pluripotent cells for the use in regenerative medicine, pharmaceutical screening, and disease modeling. In some cases, prenatal diagnosis allows isolation of hAFSCs from fetuses with chromosomal anomalies and their use could provide a unique opportunity for the modeling of genetic diseases and to predict the outcome of several pathologies [40]. In this regard, in the same year, interesting results have clearly demonstrated that [beta]-thalassemia patient-specific autologous induced pluripotent stem cells can be rapidly and efficiently generated from cultured terminally differentiated AFSCs using a single excisable lentiviral stem cell cassette [41]. In addition, AFSCs with trisomy 21 have been used to obtain iPSCs in modeling of Down syndrome and hence impaired neurogenesis has been observed [42]. However, in all these studies, virus-based integrating reprogramming approach was used but the risk of insertional mutagenesis into the cell genome is very high. To address this issue, numerous strategies constituted by the PiggyBac (PB) transposon system and chemically defined culture have been developed [43, 44] for eventual clinical translation of hAFiPSCs into cell therapies. In this regard, one study provides compelling evidence on the possibility to generate a population of beating amniotic fluid-derived cardiomyocytes (AF-CMs) after Sendai virus reprogramming towards pluripotency [45]. Similar data were confirmed by other groups that have focused their attention on possibility to obtain functional cardiomyocytes from iPSC reprogramming using nonviral methods [46]. Taken together, these findings provide evidences that amniotic fluid (AF) could represent an ideal source for autologous cells for the treatment of neonatal congenital heart defects and neurodegenerative diseases. In particular, Qin et al. have evaluated AFiPSC membrane-derived vesicles for repairing of cerebral ischemic damage and in addition to it, they have demonstrated the generation of AFiPSCs with ectopic expression of the transcription factor Oct4 alone [47]. Recently, the suitability of the AFSCs in reprogramming application for the generation of iPSCs and subsequent differentiation into haematopoietic and neural lineages was identified [48]. In line with these promising findings, there is an increasing interest in the possibility of cultivating AFSCs from fetuses affected by genetic diseases in order to study the processes of tissue differentiation in pathological conditions [23, 40] and to generate disease modeling by applying reprogramming technologies.

3. MicroRNA Profiling of hAFSCs: Key

Regulators of Self-Renewal, Differentiation, and Proliferation

MicroRNAs or miRNAs belong to a class of highly conserved small noncoding RNAs (18-25 nucleotides in length) that play a key role in posttranscriptional gene regulation in many organisms [49, 50]. In mammals, miRNAs are also involved in the early maturation of embryos, stem cell differentiation, and apoptosis [51-53]. The outstanding roles of miRNAs in stem cells have been investigated in a wide range of biological processes, including self-renewal, differentiation, and proliferation [54]. Since miRNAs can repress the translation of many mRNA targets, they are ideal candidates to regulate cell fates [55]. A large body of evidences suggests that miRNAs in the amniotic fluid (AF) act as modulators to regulate the expression of specific genes during fetal development [56, 57]. It is important to emphasize that the components of AF are mainly derived from the fetus and the presence of specific microRNAs may be able to give important information on fetal development, physiology, and pathology during pregnancy [58-60]. In this scenario, growing interest has focused on epigenetic properties of hAFSCs in order to identify new markers of stemness, self-renewal, and differentiation. Current literature data show that miRNAs play a crucial role in the fate of hAFSCs and in particular they are involved in controlling the WNT signaling, MAPK signaling, and TGF-[beta] signaling pathways [61]. In addition, a first characterization of the regenerative potential of the hAFSC-derived extracellular vesicles (EV) has identified specific miRNAs involved in their paracrine effects [62].

These results are coherent with previous findings, which reported that specific miRNAs (miR-146a and miR-10a) obtained from hAFSC-derived exosomes have a therapeutic effect in a mouse model of cyclophosphamide- (CTx-) induced premature ovarian failure (POF) [63]. Finally, the temporal analysis of the hAFSCs between passages 1 and 15 showed significant variation in the expression of multiple genes and miRNAs. These changes are mainly related with the downregulation of TP53 and the increased expression of hsa-miR-125a, which could act as indicators of the state of proliferative capacity and stemness [64]. Taken together, these data provide the possibility of a novel clinical cell-free therapeutic strategy for the treatment of several human diseases. Another important aspect is the involvement of small RNAs in mammalian cell differentiation. In fact, these molecules accelerate the change of cell state into progenitor cell lineages [65]. Emerging evidences demonstrate that in in vivo, the microenvironment decides the fate of multipotent, pluripotent, or totipotent cells, towards the commitment into a specific lineage [66, 67]. However, there are very less shreds of evidences explaining how the microenvironment precisely changes the character and properties of the cells, changing it from one morphological state of stem cells to another morphological state of differentiated cells. With the advances in in vitro, cell culture and molecular techniques, a number of factors responsible for cellular differentiation have been elucidated. With these discoveries, the most frequent questions we come across are how these differentiation factors actually carry out differentiation and what happens to the cells after they get differentiated. It is documented that hAFSCs have the remarkable potential to develop into many different cell types [42, 68, 69], but to date there is not much information regarding epigenetic changes associated with their multilineage differentiation capability. miRNA expression studies involved in the differentiation of hAFSCs have been pioneered by two researchers in 2014 when they demonstrated that these cells displayed an appreciable ability to differentiate towards osteogenic and chondrogenic lineage but failed adipogenesis, as proved by expression of miR-21, mainly implicated in osteogenesis differentiation [70, 71] (see Figure 3). These data were also confirmed by Gholizadeh-Ghaleh Aziz et al. that highlighted the possible role of miR-302a and miR-Let7g in the interaction with Nanog and POU5F1 and involvement in two differentiation processes of adipogenesis and osteogenesis [72]. Finally, as stated in the study of Glemzaite and Navakauskiene, osteogenic differentiation of hAFSCs is mediated by chromatin-modifying enzymes, histone modifications, and specific microRNA expression [73] (see Table 1). These observations suggest the importance of miRNAs in the regulation of AFSC fate and reinforce the necessity of further studies to investigate their potential therapeutic applications in the field of regenerative medicine.

4. Epigenetic Markers of Fetus-Affected Pregnancies

Current research has focused on the role of epigenetic processes in embryo development and growth, in particular on the enhanced susceptibility to fetal diseases. In recent years, there is an explosion of research in the field of "environmental epigenomics" based on the relationships between environmental exposures, epigenetics, and human health and diseases [74, 75]. The prenatal period represents a critical period of development during which adverse conditions and environmental exposures may influence offspring health and behavioral outcomes [76, 77]. One of the most intriguing aspects of epigenetic research is the concept of transgenerational inheritance. This phenomenon explains that some epigenetic changes occurring in the germline have the potential to be transmitted to the offspring. In support of this notion, it has been recently shown that AFSCs share several features with primordial germ cells (PGCs) [24], thus suggesting their use as an efficient handy tool to study human gametogenesis and understand the diseases caused by epigenetic alterations endangering transgenerational inheritance [40]. In some cases, prenatal diagnosis allows the detection of genetic diseases and the use of AFSCs could provide a very interesting model to understand the molecular basis of pathologies and to identify new therapeutic approaches [23, 40]. In this scenario, in 2013, Tsurubuchi et al. published data describing the presence of novel biomarkers for early detection of neural tube defects (NTDs) in human fetuses. This study examined the expression of epigenetic histone marks in hAFSCs cultured from women pregnant with normal or NTD-affected fetuses. In detail, stem cells obtained from the anencephaly-affected pregnancy showed higher levels of H3K4me2/me3 and H3K27me2/me3 together with lower levels of H3K9ac and H3K18ac in cultures [78]. This is a first step in the identification of novel biomarkers for NTDs, and in the future, these epigenetic marks could be tested in the blood of pregnant women in order to develop specific treatments for in utero closure of these defects. In addition, epigenetic factors are implicated in senescence process of AFSCs and a diversity of proliferation and senescence of cells from AF of normal gestation and fetus abnormalities has recently been reported. The two sample groups showed different dynamic changes in chromatin structure during cell senescence. In particular, it was reported that stem cells derived from AF with fetus abnormalities led to senescence in rather early passages (from 5 to 8) and showed the changes in morphological and senescence associated with repressive histone modifications (H3K9me3 and H3K27me3) [79]. In 2017, the same researchers performed further experiments to better understand the epigenetic environment in terms of histone modifications in hAFSC cultures in normal and diseased gestation conditions. The comparison of healthy and pathological samples revealed that two distinct cultures especially with regard to the proliferation potential of hAFSCs from some donors with genetic or multifactorial fetal diseases displayed distinct growth, the alterations in global DNA methylation, changes in the pattern of acetylated histones H3 and H4, and dysregulation of both methylated histones H3K27 and H3K9 [80]. Considering the fact that to date epigenetic mechanisms in abnormal prenatal conditions are not well known, these results lay the foundation for identifying novel biomarkers for human diseases in the serum of pregnant women (see Figure 4). A very interesting recent paper described the presence of significantly dysregulated miRNAs in AFSCs from pregnant women carrying fetuses with Down syndrome (DS). In the future, these findings may provide valuable insights regarding the use of miRNAs in the prenatal diagnosis of DS (see Table 2). Nevertheless, the association between miRNAs encoded by chromosome 21 and the various phenotypes of DS should be further investigated before their diagnostic application [81].

5. Status of Genomic Imprinting of Human AFSCs

The genomic imprinting represents a non-Mendelian heredity model and is a process of "marking" of some genes preferentially expressed from a single parental allele. Imprinted genes exert broad roles and influence fetal growth, pluripotency, differentiation, and behavior [82]. Scientific evidence suggests that dysregulation of imprinted gene dosage can be involved with tumorigenesis and altered cell differentiation ability [83, 84]. In humans, abnormal imprinting patterns are associated with congenital disorders, including Beckwith-Wiedemann, Silver-Russell, Angelman, and Prader-Willi syndromes [85, 86]. Several studies have previously tested the status of imprinted genes in hESCs, suggesting that SNRPN, IPW, and KCNQ1OT1 were highly stable and insensitive to epigenetic perturbations. In contrast, H19, IGF2, and MEG3 were more variable and could provide an indication of epigenetic status [87-89]. These evidences confirm that hESC lines expressing monoallelic gene after differentiation may be better suited to therapeutic use than lines that show variable expression. There is a growing attention in the study of alterations of imprinted genes in hAFSCs during in vitro cell culture. Unfortunately, until now, there is no extensive literature documenting the changes in expression of genomic imprinting of these cells. In 2012, the first study on alterations of imprinted genes (H19, SNRPN, and KCNQ1OT1) in hAFSCs was performed by Peng et al. In particular, it was observed that during in vitro hAFSC culture, there are hypermethylation of H19 and KCNQ1OT1 and variable DNA methylation patterns in the SNRPN gene [90]. These results were in agreement with the study by Phermthai et al. which demonstrated the aberrant expression of the IGF2 and H19 genes in late passages of AFSCs [91]. On the basis of these preliminary observations, it can be assumed that the epigenetic instability correlates with the loss of differentiation potential in late passages of AFSCs, and due to this reason, the therapeutic use of these cells should be limited to the 8th passages. Most recently, epigenetic analysis showed that AF is one of the most interesting sources for medical therapy because AFSCs display high genomic stability and epigenetic fidelity [84]. These data reinforce the necessity of further studies to investigate the therapeutic potential of hAFSCs and support their use in the clinical therapy.

6. Conclusions

The surprising picture that has emerged in the past few years is the therapeutic potential of hAFSCs in the field of regenerative medicine and the possibility to develop novel strategies against a wide range of human disorders. The progresses of preclinical experiments are encouraging but important aspects should be explored in order to support the use of hAFSCs in the clinical application in the near future. In this scenario, the molecular characterization of these cells has a relevant importance as they can be used in regenerative medicine. In this review, we have focused on the current knowledge concerning the role of epigenetic changes in proliferation, differentiation of hAFSCs, and biomarkers involved in diseased gestation conditions. The potential use of AFSCs for tissue regeneration was shown to be successful in animal models, and elucidating their differentiation process is fundamental to avoid undesired side effects in future clinical applications. To date, little is known on histone and DNA methylation modifications of hAFSCs but some data support the notion that epigenetic machinery by histone modifications and chromatin remodeling is involved during osteogenic and adipogenic differentiation. Another interesting feature is represented by the possibility to cultivate these cells from affected fetuses in order to study the molecular mechanism underlying the development of congenital malformation. In this aspect, hAFSCs could represent an interesting alternative to iPSCs for identifying epigenetic marks in diseased gestation. On the basis of preliminary observations, these markers could be used for early detection and future identification of abnormal prenatal conditions in amniotic fluid and maternal serum. In consideration of data described in the present review, it is possible to conclude that epigenetic modifications are involved in the following:

(i) Self-renewal and differentiation of AFSCs

(ii) The generation of iPSCs from human AFSCs

(iii) Fetal cell cultures associated with the genetic disease

(iv) Studies of transgenerational inheritance

Finally, further investigations should be conducted to define a better comprehension of "epigenetic landscape" of hAFSCs in order to expedite the progress of stem cell-based therapeutics in regenerative medicine.

https://doi.org/10.1155/2018/4274518

Conflicts of Interest

The authors declare no conflict of interest.

Authors' Contributions

Daniela Di Tizio wrote the Status of Genomic Imprinting of Human AFSCs and conceived the figures. Alessandra Di Serafino wrote the MicroRNA Profiling of hAFSCs: Key Regulators of Self-Renewal, Differentiation, and Proliferation and conceived the figures. Prabin Upadhyaya wrote the Epigenetic Changes in AFSC Reprogramming and conceived the figures. Luca Sorino wrote the Epigenetic Markers of Fetus-Affected Pregnancies. Liborio Stuppia and Ivana Antonucci wrote the background and supervised the editing of the manuscript.

Acknowledgments

This study was supported by grants from the Ministry of Education, University and Research (MIUR) 2015 prot. 20157FF4KM_002 to Liborio Stuppia.

References

[1] K. Ohbo and S. Tomizawa, "Epigenetic regulation in stem cell development, cell fate conversion, and reprogramming," Biomolecular Concepts, vol. 6, no. 1, pp. 1-9, 2015.

[2] L. Morey, A. Santanach, and L. Di Croce, "Pluripotency and epigenetic factors in mouse embryonic stem cell fate regulation," Molecular and Cellular Biology, vol. 35, no. 16, pp. 2716-2728, 2015.

[3] T. Vougiouklakis, Y. Nakamura, and V. Saloura, "Critical roles of protein methyltransferases and demethylases in the regulation of embryonic stem cell fate," Epigenetics, vol. 12, no. 12, pp. 1015-1027, 2018.

[4] R. D. Thiagarajan, R. Morey, and L. C. Laurent, "The epigenome in pluripotency and differentiation," Epigenomics, vol. 6, no. 1, pp. 121-137, 2014.

[5] T. Miyamoto, C. Furusawa, and K. Kaneko, "Pluripotency, differentiation, and reprogramming: a gene expression dynamics model with epigenetic feedback regulation," PLoS Computational Biology, vol. 11, no. 8, article e1004476, 2015.

[6] E. Coskun, M. Ercin, and S. Gezginci-Oktayoglu, "The role of epigenetic regulation and pluripotency-related microRNAs in differentiation of pancreatic stem cells to beta cells," Journal of Cellular Biochemistry, vol. 119, no. 1, pp. 455-467, 2018.

[7] M. Nakagawa and O. Narikiyo, "Epigenetic landscape of interacting cells: a model simulation for developmental process," Bio Systems, vol. 101, no. 3, pp. 156-161, 2010.

[8] K. Hochedlinger and R. Jaenisch, "Induced pluripotency and epigenetic reprogramming," Cold Spring Harbor Perspectives in Biology, vol. 7, no. 12, article a019448, 2015.

[9] C.-H. Lou, J. Dumdie, A. Goetz et al., "Nonsense-mediated RNA decay influences human embryonic stem cell fate," Stem Cell Reports, vol. 6, no. 6, pp. 844-857, 2016.

[10] D. S. Kim, M. W. Lee, T.-H. Lee, K. W. Sung, H. H. Koo, and K. H. Yoo, "Cell culture density affects the stemness gene expression of adipose tissue-derived mesenchymal stem cells," Biomedical Reports, vol. 6, no. 3, pp. 300-306, 2017.

[11] F. Balzano, S. Cruciani, V. Basoli et al., "MiR200 and miR302: two big families influencing stem cell behavior," Molecules, vol. 23, no. 2, p. 282, 2018.

[12] J. Bem, I. Grabowska, M. Daniszewski et al., "Transient microRNA expression enhances myogenic potential of mouse embryonic stem cells," Stem Cells, vol. 36, no. 5, pp. 655-670, 2018.

[13] P. du, M. Pirouz, J. Choi et al., "An intermediate pluripotent state controlled by microRNAs is required for the naive-to-primed stem cell transition," Cell Stem Cell, vol. 22, no. 6, pp. 851-864.e5, 2018.

[14] J. Tu, D. Cao, L. Li, H.-H. Cheung, and W.-Y. Chan, "MicroRNA profiling during directed differentiation of cortical interneurons from human-induced pluripotent stem cells," FEBS Open Bio, vol. 8, no. 4, pp. 502-512, 2018.

[15] J.-J. Yuan, F. Qin, J.-L. Tu, and B. Li, "Preparation, characterization, and antioxidant activity evaluation of liposomes containing water-soluble hydroxytyrosol from olive," Molecules, vol. 22, no. 6, p. 870, 2017.

[16] Y. J. Lee, S. Ramakrishna, H. Chauhan, W. S. Park, S. H. Hong, and K. S. Kim, "Dissecting microRNA-mediated regulation of stemness, reprogramming, and pluripotency," Cell Regeneration, vol. 5, no. 1, p. 5:2, 2016.

[17] A. J. Bannister and T. Kouzarides, "Regulation of chromatin by histone modifications," Cell Research, vol. 21, no. 3, pp. 381-395, 2011.

[18] F. Baluska and G. Witzany, "Life is more than a computer running DNA software," World Journal of Biological Chemistry, vol. 5, no. 3, pp. 275-278, 2014.

[19] S. Joo, I. K. Ko, A. Atala, J. J. Yoo, and S. J. Lee, "Amniotic fluid-derived stem cells in regenerative medicine research," Archives of Pharmacal Research, vol. 35, no. 2, pp. 271-280, 2012.

[20] C. D. Dolin, M. K. Chan, R. S. Basch, and B. K. Young, "Human term amniotic fluid: a novel source of stem cells for regenerative medicine," American Journal of Obstetrics and Gynecology, vol. 219, no. 3, pp. 308-309, 2018.

[21] M. Srivastava, N. Ahlawat, and A. Srivastava, "Amniotic fluid stem cells: a new era in regenerative medicine," Journal of Obstetrics and Gynaecology of India, vol. 68, no. 1, pp. 15-19, 2018.

[22] P. de Coppi, G. Bartsch, M. M. Siddiqui et al., "Isolation of amniotic stem cell lines with potential for therapy," Nature Biotechnology, vol. 25, no. 1, pp. 100-106, 2007.

[23] I. Antonucci, A. Pantalone, S. Tete et al., "Amniotic fluid stem cells: a promising therapeutic resource for cell-based regenerative therapy," Current Pharmaceutical Design, vol. 18, no. 13, pp. 1846-1863, 2012.

[24] I. Antonucci, R. di Pietro, M. Alfonsi et al., "Human second trimester amniotic fluid cells are able to create embryoid body-like structures in vitro and to show typical expression profiles of embryonic and primordial germ cells," Cell Transplantation, vol. 23, no. 12, pp. 1501-1515, 2014.

[25] V. Spinelli, P. V. Guillot, and P. De Coppi, "Induced pluripotent stem (iPS) cells from human fetal stem cells (hFSCs)," Organogenesis, vol. 9, no. 2, pp. 101-110, 2014.

[26] E. Borrelli, E. J. Nestler, C. D. Allis, and P. Sassone-Corsi, "Decoding the epigenetic language of neuronal plasticity," Neuron, vol. 60, no. 6, pp. 961-974, 2008.

[27] C. Li, J. Zhou, G. Shi et al., "Pluripotency can be rapidly and efficiently induced in human amniotic fluid-derived cells," Human Molecular Genetics, vol. 18, no. 22, pp. 4340-4349, 2009.

[28] K. Wolfrum, Y. Wang, A. Prigione, K. Sperling, H. Lehrach, and J. Adjaye, "The LARGE principle of cellular reprogramming: lost, acquired and retained gene expression in foreskin and amniotic fluid-derived human iPS cells," PLoS One, vol. 5, no. 10, article e13703, 2010.

[29] K. Drews, P. Matz, and J. Adjaye, "Generation of iPSC lines from primary human amniotic fluid cells," Stem Cell Research, vol. 15, no. 3, pp. 712-714, 2015.

[30] M. Gladych, A. Andrzejewska, U. Oleksiewicz, and M. R. H. Estecio, "Review epigenetic mechanisms of induced pluripotency," Wspolczesna Onkologia, vol. 19, no. 1A, pp. 30-38, 2015.

[31] J. Brix, Y. Zhou, and Y. Luo, "The epigenetic reprogramming roadmap in generation of iPSCs from somatic cells," Journal of Genetics and Genomics, vol. 42, no. 12, pp. 661-670, 2015.

[32] L. Ringrose and R. Paro, "Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins," Annual Review of Genetics, vol. 38, no. 1, pp. 413-443, 2004.

[33] K. Nishino, M. Toyoda, M. Yamazaki-Inoue et al., "DNA methylation dynamics in human induced pluripotent stem cells over time," PLoS Genetics, vol. 7, no. 5, article e1002085, 2011.

[34] Y.-S. Ang, S.-Y. Tsai, D.-F. Lee et al., "Wdr5 mediates selfrenewal and reprogramming via the embryonic stem cell core transcriptional network," Cell, vol. 145, no. 2, pp. 183-197, 2011.

[35] J. Chen, H. Liu, J. Liu et al., "H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs," Nature Genetics, vol. 45, no. 1, pp. 34-42, 2013.

[36] S. Epsztejn-Litman, N. Feldman, M. Abu-Remaileh et al., "De novo DNA methylation promoted by G9a prevents reprogramming of embryonically silenced genes," Nature Structural & Molecular Biology, vol. 15, no. 11, pp. 1176-1183, 2008.

[37] A. Soufi, G. Donahue, and K. S. Zaret, "Facilitators and impediments of the pluripotency reprogramming factors' initial engagement with the genome," Cell, vol. 151, no. 5, pp. 994-1004, 2012.

[38] R. D. Hawkins, G. C. Hon, L. K. Lee et al., "Distinct epigenomic landscapes of pluripotent and lineage-committed human cells," Cell Stem Cell, vol. 6, no. 5, pp. 479-491, 2010.

[39] D. Moschidou, S. Mukherjee, M. P. Blundell et al., "Valproic acid confers functional pluripotency to human amniotic fluid stem cells in a transgene-free approach," Molecular Therapy, vol. 20, no. 10, pp. 1953-1967, 2012.

[40] I. Antonucci, M. Provenzano, M. Rodrigues et al., "Amniotic fluid stem cells: a novel source for modeling of human genetic diseases," International Journal of Molecular Sciences, vol. 17, no. 4, p. 607, 2016.

[41] Y. Fan, Y. Luo, X. Chen, Q. Li, and X. Sun, "Generation of human [beta]-thalassemia induced pluripotent stem cells from amniotic fluid cells using a single excisable lentiviral stem cell cassette," The Journal of Reproduction and Development, vol. 58, no. 4, pp. 404-409, 2012.

[42] H.-E. Lu, Y.-C. Yang, S.-M. Chen et al., "Modeling neurogenesis impairment in Down syndrome with induced pluripotent stem cells from trisomy 21 amniotic fluid cells," Experimental Cell Research, vol. 319, no. 4, pp. 498-505, 2013.

[43] E. Bertin, M. Piccoli, C. Franzin et al., "Reprogramming of mouse amniotic fluid cells using a PiggyBac transposon system," Stem Cell Research, vol. 15, no. 3, pp. 510-3, 2015.

[44] J. Slamecka, L. Salimova, S. McClellan et al., "Non-integrating episomal plasmid-based reprogramming of human amniotic fluid stem cells into induced pluripotent stem cells in chemically defined conditions," Cell Cycle, vol. 15, no. 2, pp. 234-249, 2015.

[45] G. Jiang, T. J. Herron, J. di Bernardo, K. A. Walker, K. S. O'Shea, and S. M. Kunisaki, "Human cardiomyocytes prior to birth by integration-free reprogramming of amniotic fluid cells," Stem Cells Translational Medicine, vol. 5, no. 12, pp. 1595-1606, 2016.

[46] A. J. Velasquez-Mao, C. J. M. Tsao, M. N. Monroe et al., "Differentiation of spontaneously contracting cardiomyocytes from non-virally reprogrammed human amniotic fluid stem cells," PLoS One, vol. 12, no. 5, article e0177824, 2017.

[47] M. Qin, R. Chen, H. Li et al., "Direct reprogramming of human amniotic fluid stem cells by OCT4 and application in repairing of cerebral ischemia damage," International Journal of Biological Sciences, vol. 12, no. 5, pp. 558-568, 2016.

[48] R. Moraghebi, A. Kirkeby, P. Chaves et al., "Term amniotic fluid: an unexploited reserve of mesenchymal stromal cells for reprogramming and potential cell therapy applications," Stem Cell Research & Therapy, vol. 8, no. 1, p. 190, 2017.

[49] Y. Cai, X. Yu, S. Hu, and J. Yu, "A brief review on the mechanisms of miRNA regulation," Genomics, Proteomics & Bioinformatics, vol. 7, no. 4, pp. 147-154, 2009.

[50] D. P. Bartel, "MicroRNAs: genomics, biogenesis, mechanism, and function," Cell, vol. 116, no. 2, pp. 281-297, 2004.

[51] K. Qu, Z. Wang, X. Lin, K. Zhang, X. L. He, and H. Zhang, "MicroRNAs: key regulators of endothelial progenitor cell functions," Clinica Chimica Acta, vol. 448, pp. 65-73, 2015.

[52] J. Krol, I. Loedige, and W. Filipowicz, "The widespread regulation of microRNA biogenesis, function and decay," Nature Reviews Genetics, vol. 11, no. 9, pp. 597-610, 2010.

[53] D. P. Bartel, "MicroRNAs: target recognition and regulatory functions," Cell, vol. 136, no. 2, pp. 215-233, 2009.

[54] S. W. Choi, J. Y. Lee, and K. S. Kang, "miRNAs in stem cell aging and age-related disease," Mechanisms of Ageing and Development, vol. 168, pp. 20-29, 2017.

[55] J. Mathieu and H. Ruohola-Baker, "Regulation of stem cell populations by microRNAs," Advances in Experimental Medicine and Biology, vol. 786, pp. 329-351, 2013.

[56] B. D. Kamath-Rayne, H. C. Smith, L. J. Muglia, and A. L. Morrow, "Amniotic fluid: the use of high-dimensional biology to understand fetal well-being," Reproductive Sciences, vol. 21, no. 1, pp. 6-19, 2013.

[57] T. Sun, W. Li, T. Li, and S. Ling, "microRNA profiling of amniotic fluid: evidence of synergy of microRNAs in fetal development," PLoS One, vol. 11, no. 5, article e0153950, 2016.

[58] D. K. Slonim, K. Koide, K. L. Johnson et al., "Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses," Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 23, pp. 9425-9429, 2009.

[59] L. J. Massingham, K. L. Johnson, T. M. Scholl, D. K. Slonim, H. C. Wick, and D. W. Bianchi, "Amniotic fluid RNA gene expression profiling provides insights into the phenotype of Turner syndrome," Human Genetics, vol. 133, no. 9, pp. 1075-1082, 2014.

[60] L. Hui, D. K. Slonim, H. C. Wick, K. L. Johnson, and D. W. Bianchi, "The amniotic fluid transcriptome," Obstetrics & Gynecology, vol. 119, no. 1, pp. 111-118, 2012.

[61] R. Lazzarini, G. Sorgentoni, M. Caffarini et al., "New miRNAs network in human mesenchymal stem cells derived from skin and amniotic fluid," International Journal of Immunopathology and Pharmacology, vol. 29, no. 3, pp. 523-528, 2016.

[62] C. Balbi, M. Piccoli, L. Barile et al., "First characterization of human amniotic fluid stem cell extracellular vesicles as a powerful paracrine tool endowed with regenerative potential," Stem Cells Translational Medicine, vol. 6, no. 5, pp. 1340-1355, 2017.

[63] G.-Y. Xiao, C.-C. Cheng, Y.-S. Chiang, W. T.-K. Cheng, I.H. Liu, and S.-C. Wu, "Exosomal miR-10a derived from amniotic fluid stem cells preserves ovarian follicles after chemotherapy," Scientific Reports, vol. 6, no. 1, article 23120, 2016.

[64] J. M. Miranda-Sayago, N. Fernandez-Arcas, A. Reyes-Engel, C. Benito, I. Narbona, and A. Alonso, "Changes in CDKN2D, TP53, and miR125a expression: potential role in the evaluation of human amniotic fluid-derived mesenchymal stromal cell fitness," Genes to Cells: Devoted to Molecular & Cellular Mechanisms, vol. 17, no. 8, pp. 673-687, 2012.

[65] J. Shim and J.-W. Nam, "The expression and functional roles of microRNAs in stem cell differentiation," BMB Reports, vol. 49, no. 1, pp. 3-10, 2016.

[66] S. Atkinson and L. Armstrong, "Epigenetics in embryonic stem cells: regulation of pluripotency and differentiation," Cell and Tissue Research, vol. 331, no. 1, pp. 23-29, 2008.

[67] I. Mortada and R. Mortada, "Epigenetic changes in mesenchymal stem cells differentiation," European Journal of Medical Genetics, vol. 61, no. 2, pp. 114-118, 2018.

[68] I. Antonucci, I. Iezzi, E. Morizio et al., "Isolation of osteogenic progenitors from human amniotic fluid using a single step culture protocol," BMC Biotechnology, vol. 9, no. 1, p. 9, 2009.

[69] I. D'Alimonte, A. Lannutti, C. Pipino et al., "Wnt signaling behaves as a "master regulator" in the osteogenic and adipogenic commitment of human amniotic fluid mesenchymal stem cells," Stem Cell Reviews, vol. 9, no. 5, pp. 642-654, 2013.

[70] O. Trohatou, D. Zagoura, V. Bitsika et al., "Sox2 suppression by miR-21 governs human mesenchymal stem cell properties," Stem Cells Translational Medicine, vol. 3, no. 1, pp. 54-68, 2014.

[71] R. Lazzarini, F. Olivieri, C. Ferretti, M. Mattioli-Belmonte, R. di Primio, and M. Orciani, "mRNAs and miRNAs profiling of mesenchymal stem cells derived from amniotic fluid and skin: the double face of the coin," Cell and Tissue Research, vol. 355, no. 1, pp. 121-130, 2014.

[72] S. Gholizadeh-Ghaleh Aziz, F. Pashaei-Asl, Z. Fardyazar, and M. Pashaiasl, "Isolation, characterization, cryopreservation of human amniotic stem cells and differentiation to osteogenic and adipogenic cells," PLoS One, vol. 11, no. 7, article e0158281, 2016.

[73] M. Glemzaite and R. Navakauskiene, "Osteogenic differentiation of human amniotic fluid mesenchymal stem cells is determined by epigenetic changes," Stem Cells International, vol. 2016, Article ID 6465307, 10 pages, 2016.

[74] C. J. Marsit, "Influence of environmental exposure on human epigenetic regulation," Journal of Experimental Biology, vol. 218, no. 1, pp. 71-79, 2015.

[75] G. Lippi and G. Cervellin, "The interplay between genetics, epigenetics and environment in modulating the risk of coronary heart disease," Annals of Translational Medicine, vol. 4, no. 23, pp. 460-460, 2016.

[76] L. Stuppia, M. Franzago, P. Ballerini, V. Gatta, and I. Antonucci, "Epigenetics and male reproduction: the consequences of paternal lifestyle on fertility, embryo development, and children lifetime health," Clinical Epigenetics, vol. 7, no. 1, p. 120, 2015.

[77] V. S. Knopik, K. Marceau, L. C. Bidwell, and E. Rolan, "Prenatal substance exposure and offspring development: does DNA methylation play a role?," Neurotoxicology and Teratology, 2018.

[78] T. Tsurubuchi, S. Ichi, K. Shim et al., "Amniotic fluid and serum biomarkers from women with neural tube defect-affected pregnancies: a case study for myelomeningocele and anencephaly: clinical article," Journal of Neurosurgery. Pediatrics, vol. 12, no. 4, pp. 380-389, 2013.

[79] J. Savickiene, S. Baronaite, A. Zentelyte, G. Treigyte, and R. Navakauskiene, "Senescence-associated molecular and epigenetic alterations in mesenchymal stem cell cultures from amniotic fluid of normal and fetus-affected pregnancy," Stem Cells International, vol. 2016, Article ID 2019498, 13 pages, 2016.

[80] J. Savickiene, D. Matuzevicius, S. Baronaite et al., "Histone modifications pattern associated with a state of mesenchymal stem cell cultures derived from amniotic fluid of normal and fetus-affected gestations," Journal of Cellular Biochemistry, vol. 118, no. 11, pp. 3744-3755, 2017.

[81] E. Karaca, A. Aykut, B. Erturk et al., "MicroRNA expression profile in the prenatal amniotic fluid samples of pregnant women with Down syndrome," Balkan Medical Journal, vol. 35, no. 2, pp. 163-166, 2018.

[82] R. N. Plasschaert and M. S. Bartolomei, "Genomic imprinting in development, growth, behavior and stem cells," Development, vol. 141, no. 9, pp. 1805-1813, 2014.

[83] A. C. Ferguson-Smith, "Genomic imprinting: the emergence of an epigenetic paradigm," Nature Reviews Genetics, vol. 12, no. 8, pp. 565-575, 2011.

[84] M. M. Patten, M. Cowley, R. J. Oakey, and R. Feil, "Regulatory links between imprinted genes: evolutionary predictions and consequences," Proceedings of the Royal Society B: Biological Sciences, vol. 283, no. 1824, article 20152760, 2016.

[85] S. J. Chamberlain, P. F. Chen, K. Y. Ng et al., "Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader-Willi syndromes," Proceedings of the National Academy of Sciences, vol. 107, no. 41, pp. 17668-17673, 2010.

[86] J. M. Kalish, C. Jiang, and M. S. Bartolomei, "Epigenetics and imprinting in human disease," The International Journal of Developmental Biology, vol. 58, no. 2-3-4, pp. 291-298, 2014.

[87] J. Lee, A. Matsuzawa, H. Shiura, A. Sutani, and F. Ishino, "Preferable in vitro condition for maintaining faithful DNA methylation imprinting in mouse embryonic stem cells," Genes to Cells, vol. 23, no. 3, pp. 146-160, 2018.

[88] S. S. Li, S. L. Yu, and S. Singh, "Epigenetic states and expression of imprinted genes in human embryonic stem cells," World Journal of Stem Cells, vol. 2, no. 4, pp. 97-102, 2010.

[89] P. J. Rugg-Gunn, A. C. Ferguson-Smith, and R. A. Pedersen, "Status of genomic imprinting in human embryonic stem cells as revealed by a large cohort of independently derived and maintained lines," Human Molecular Genetics, vol. 16, no. R2, pp. R243-R251, 2007.

[90] H.-H. Peng, S.-D. Chang, A.-S. Chao et al., "DNA methylation patterns of imprinting centers for H19, SNRPN, and KCNQ1OT1 in single-cell clones of human amniotic fluid mesenchymal stem cell," Taiwanese Journal of Obstetrics and Gynecology, vol. 51, no. 3, pp. 342-349, 2012.

[91] T. Phermthai, S. Suksompong, N. Tirawanchai et al., "Epigenetic analysis and suitability of amniotic fluid stem cells for research and therapeutic purposes," Stem Cells and Development, vol. 22, no. 9, pp. 1319-1328, 2013.

[92] M. T. Pinto, L. D. F. Nicolete, E. S. Rodrigues et al., "Overexpression of hsa-miR-125b during osteoblastic differentiation does not influence levels of Runx2, osteopontin, and ALPL gene expression," Brazilian Journal of Medical and Biological Research, vol. 46, no. 8, pp. 676-680, 2013.

Daniela Di Tizio, Alessandra Di Serafino, Prabin Upadhyaya, Luca Sorino, Liborio Stuppia, and Ivana Antonucci [ID]

Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, "G. d'Annunzio" University, Chieti-Pescara, Italy

Correspondence should be addressed to Ivana Antonucci; i.antonucci@unich.it

Received 4 July 2018; Accepted 4 October 2018; Published 25 November 2018

Academic Editor: Federico Mussano

Caption: Figure 1: Epigenetic mechanisms implicated in the self-renewal, differentiation, and proliferation of hAFCS.

Caption: Figure 2: Epigenetic modifications induced by methylation and acetylation of H3 and H4.

Caption: Figure 3: Several applications of hAFSCs for different biological and molecular studies.

Caption: Figure 4: The role of miRNAs in hAFSCs during chondrogenic, osteogenic, and adipogenic differentiation.
Table 1: Epigenetic regulation of osteogenic and adipogenic
differentiation of AFSCs.

Epigenetic changes               Effect of alteration

miR-125b              Overexpression during osteoblastic
                      differentiation

miR-21                Overexpression during osteoblastic
                      and adipogenic differentiation

miR-302a and miR-     Upregulation of miR-302a and downregulation
Let7g                 of miR-Let7g in AFSCs

H3K9ac, H4 hyperAc,   Upregulation of acetylation of H3K9 and H4,
H3K27me3, miR-17,     reduction of H3K27me3, and upregulation of
and miR-148b          miR-17 and miR-148b in osteogenic
                      differentiation

Epigenetic changes                  Finding                  Reference

miR-125b              Does not influence levels of Runx2,      [92]
                      osteopontin, and ALPL gene
                      expression

miR-21                Accelerates osteogenesis and             [70]
                      decelerates adipogenesis

miR-302a and miR-     Interact with Nanog and POUSF1 and       [72]
Let7g                 are involved in adipogenesis and
                      osteogenesis differentiation

H3K9ac, H4 hyperAc,   Osteogenic differentiation is            [73]
H3K27me3, miR-17,     related to histone modifications and
and miR-148b          specific microRNA expression

Table 2: Associations between epigenetic modifications and diseased
gestation condition.

                 Epigenetic
Disease             marks               Alteration            Reference

Neural tube        Histone         (i) Myelomeningocele         [78]
defects                        (a) High levels of H3K4me2,
                                         H3K4me3,
                                 H3K27me2, and H3K27me3;
                                 (b) Low levels of KDM6B;
                                 (c) Decreased levels of
                                         H3K9ac,
                                    H3K18ac, and Gcn5.
                                    (ii) Anencephalic
                                 (a) increased levels of
                                    H3K27me3, H3K9Ac,
                                    H3K18Ac, and Gcn5.
Fetus-affected   Global DNA     Alterations in global DNA       [80]
pregnancies      methylation      methylation, H4K16ac,
                   histone       H3K9ac, and H3K14ac and
                                    dysregulation of
                                 H3K9me2/me3 and H3K27me3

Down syndrome     MicroRNA     High levels of miR-125b-2,       [81]
(DS)                            miR-155, and miR-3156 in
                                 pregnant women carrying
                                     fetuses with DS
COPYRIGHT 2018 COPYRIGHT 2010 SAGE-Hindawi Access to Research
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2018 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Di Tizio, Daniela; Di Serafino, Alessandra; Upadhyaya, Prabin; Sorino, Luca; Stuppia, Liborio; Anton
Publication:Stem Cells International
Date:Jan 1, 2018
Words:6967
Previous Article:The Effect of Chronic Inflammation and Oxidative and Endoplasmic Reticulum Stress in the Course of Metabolic Syndrome and Its Therapy.
Next Article:Stem Cells in Dentistry: Types of Intra- and Extraoral Tissue-Derived Stem Cells and Clinical Applications.
Topics:

Terms of use | Privacy policy | Copyright © 2021 Farlex, Inc. | Feedback | For webmasters