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Stem Cells in Regenerative Medicine – from Laboratory to Clinical Application – the Eye Review paper DOI: https://doi.org/10.5114/ceji.2017.69360 Stem cells in regenerative medicine – from laboratory to clinical application – the eye ANNA M. DĄBROWSKA1, PIOTR SKOPIŃSKI1,2 1Department of Ophthalmology, Second Faculty of Medicine, Warsaw Medical University, Poland 2Department of Histology and Embriology, Biostructure Center, Warsaw Medical University, Poland Abstract Stem cells are currently one of the most researched and explored subject in science. They consstitue a very promising part of regenerative medicine and have many potential clinical applications. Harness- ing their ability to replicate and differentiate into many cell types can enable successful treatment of diseases that were incurable until now. There are numerous types of stem cells (e.g. ESCs, FSCs, ASCs, iPSCs) and many different methods of deriving and cultivating them in order to obtain viable materi- al. The eye is one of the most interesting targets for stem cell therapies. In this article we summarise different aspects of stem cells, discussing their characteristics, sources and methods of culture. We also demonstrate the most recent clinical applications in ophthalmology based on an extensive current literature review. Tissue engineering techniques developed for corneal limbal stem cell deficiency, age-related macular degeneration (AMD) and glaucoma are among those presented. Both laboratory and clinical aspects of stem cells are discussed. Key words: stem cells, tissue engineering, regenerative medicine, eye, biomarkers, AMD, glaucoma, limbal stem cell deficiency, ophthalmology. (Cent Eur J Immunol 2017; 42 (2):173-180) Introduction otent, derived from the inner cell mass of the blastocyst, a stage of the pre-implantation embryo, 5-6 days post-fer- Stem cells present multiple potential applications in re- tilization [2]. They generate the organism, whereas the generative medicine and are the subject of intense research surrounding trophoblast cells contribute to the placental [1]. The eye is a fascinating and promising target for stem chorion. FSCs are multipotent cells located in the foetal cell therapies because it is a relatively immunologically tissues and embryonic annexes [3]. They have been sub- privileged and surgically accessible self-contained system. Many ocular diseases such as corneal limbal stem cell de- divided into haematopoietic (blood, liver, bone marrow), ficiency, age-related macular degeneration (AMD), glau- mesenchymal (blood, liver, bone marrow, lung, kidney and coma, or retinal dystrophies could be treated with the use pancreas), endothelial (bone marrow, placenta), epithelial of tissue engineering. (liver, pancreas) and neural ones (brain, spinal cord) [4]. In this article, the authors summarise different aspects Among FSCs the greatest potential use in regenerative of stem cell therapy, discussing the nature of stem cells, medicine have stem cells found in foetal blood and in their sources and culture, and presenting the most recent placenta because they are the easiest to harvest without clinical applications in ophthalmology as well as potential harming the foetus. ASCs are multipotent tissue-resident uses in future. stem cells, also termed progenitor cells, found in fully de- veloped tissues. They reside in niches that create a special microenvironment for their replication and self-renewal. Classification Very important for regenerative medicine are cell’s plas- Stem cells are defined by their ability to regenerate ticity and ability to undergo the process of transdifferenti- multiple differentiated cell types, while retaining the ca- ation. These two refer to the ability of some cells to give pacity to self-replicate (Simonovitch et al. 1963). Those rise to cell types, formerly considered outside their normal found in vivo have different origin and can be divided into repertoire of differentiation for the location where they are 3 broad categories accordingly: embryonic (ESCs), foetal found [5]. Plasticity is the capacity of organisms or cells (FSCs) and adult stem cells (ASCs, among them mesen- to alter their phenotype in response to changes in their en- chymal stem cells – MSCs). Embryonic cells are plurip- vironment [6]. Transdifferentiation is the transformation of Correspondence: Anna M. Dąbrowska, Department of Ophthalmology, Second Faculty of Medicine, Warsaw Medical University, Poland, e-mail: [email protected] Submitted: 29.10.2016; Accepted: 25.11.2016 Central European Journal of Immunology 2017; 42(2) 173 Anna M. Dąbrowska et al. Stem cells e.g. Table 1. Human embryonic stem cell (hESCs) markers [19] Totipotent (zygote) hESCs markers SSEA3, SSEA4 glycolipid antigens ESC (embryonal) Pluripotent TRA-1-60, TRA-1-81, GCTM2, GCT343 keratan sulfate iPSC (induced) antigens FSC (fetal) CD9, Thy1 (CD90), tissue-nonspecific protein antigens Mulitipotent alkaline phosphatase, class 1 HLA ASC (adult) → e.g. MSC (mesenchymal stem cells) NANOG, POU5F1 (formerly known as strongly OCT4), TDGF1, DNMT3B, GABRB3, developmentally Oligopotent GDF3 regulated genes LSC (limbal stem cells) Unipotent Table 2. Criteria for MSCs – cell surface antigens TM (trabecular meshwork stem Express Not express cells) CD90, CD105, CD73 CD45, CD34, CD14, CD11b, Fig. 1. Different stem cells: based on their differentiation CD79α, CD19, HLA-DR potential stem cells can be described as totipotent, plurip- otent, mulitipotent, oligopotent or unipotent [9]. Totipotent stem cells derive from an early progeny of the zygote up ment before it can be used in regenerative medicine as it to the eight cell stage of the morula and have the ability resulted in teratomas formation so far [16]. to form an entire organism and the extraembryonic mem- branes [10, 11]. Pluripotent cells can differentiate into tissue from all 3 germ layers (endoderm, mesoderm, and Stem cells markers ectoderm). Multipotent stem cells may differentiate into Molecular biomarkers are used to classify and isolate tissue derived from a single germ layer such as mesen- stem cells and to monitor their differentiation state by anti- chymal stem cells which form adipose tissue, bone, and body-based techniques. The expression of certain cell surface cartilage. Oligopotent stem cells, also called tissue-resi- antigens is evidence for the cell’s potency. However, because dent stem cells, can form terminally differentiated cells of stem cells are heterogeneous in morphology, phenotype, and a specific tissue [12]. Unipotent stem cells form a single function, they need to be classified into subpopulations char- lineage (ex. spermatogonial stem cells) [1] acterised by multiple sets of molecular biomarkers [17]. Human ESCs (hESCs) have flat compact colony mor- phology. Their growth depends on FGF and TGFb sig- a non-stem cell into a different cell type or the production of nalling. In 2007, the International Stem Cell Initiative cells from a differentiated stem cell that are not related to its characterised 59 hESCs lines from 17 laboratories world- already established differentiation path [7]. wide [18]. Although the lines were not identical, presented The discovery of those processes broadened the pos- various genotypes and were derived and maintained using sibilities to derive stem cells from tissues. Takahashi and different techniques, it was observed that they all exhibited Yamanaka proved in 2006 that to reprogram a differen- similar expression patterns for several markers of human tiated cell into an embryonic-like state it is enough to embryonic stem cells (Table 1). introduce certain transcription factors into culture condi- Human iPSCs (hiPSCs) share all key features with tions [8]. Their research showed that the use of retroviral human ESCs (hESCs), however there are some concerns transduction enables somatic cell reprogramming into stem about their molecular and functional equivalence discussed cells without the need of transferring their nuclear contents later in this article. into oocytes or fusing them with embryonic stem cells. Adult tissue-derived stem cells (ASCs), such as mes- Cells derived by this new method are called induced plu- enchymal stem cells (MSCs usually derived from bone ripotent stem cells (iPSCs; Fig. 1). marrow or fat but also many other tissues [20]) are among Since 2006 the strategies for deriving iPSCs are con- the most studied and some are currently being used in the stantly being improved. DNA-free and viral-free protocols clinic. In 2006, the International Society for Cellular Ther- have been presented using recombinant proteins, messen- apy (ISCT) produced a position statement suggesting the ger RNA (mRNA) and mature microRNA (miRNA) [13- minimum criteria required to define MSCs [21]. They must 15]. There has been also first attempt of in vivo reprogram- be plastic adherent, differentiate into osteoblasts, adipo- ming which showed that it is possible to produce totipotent cytes, and chondroblasts in vitro and present appropriate iPSCs within tissues, but the technique needs major refine- cell surface antigens expression (Table 2). 174 Central European Journal of Immunology 2017; 42(2) Stem cells in regenerative medicine – from laboratory to clinical application – the eye A particular challenge for the field has been the ab- depends on the type of tissue used as a source, but also on sence of any specific marker to define MSCs, although age and sex of the donor [34-36]. a large number of different determinants have been asso- With iPSCs there are also many well-known technical ciated with them but not exclusively. In vitro characteri- problems
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