J Korean Neurosurg Soc. 2019 Sep; 62(5): 493501.
1Department of Laboratory Medicine, Korea University Ansan Hospital, Ansan, Korea
2Department of Neurosurgery, Korea University Ansan Hospital, Ansan, Korea
1Department of Laboratory Medicine, Korea University Ansan Hospital, Ansan, Korea
2Department of Neurosurgery, Korea University Ansan Hospital, Ansan, Korea
1Department of Laboratory Medicine, Korea University Ansan Hospital, Ansan, Korea
2Department of Neurosurgery, Korea University Ansan Hospital, Ansan, Korea
Received 2018 Dec 7; Revised 2019 Mar 16; Accepted 2019 Apr 22.
The generation of human induced pluripotent stem cells (iPSCs) from somatic cells using gene transfer opens new areas for precision medicine with personalized cell therapy and encourages the discovery of essential platforms for targeted drug development. iPSCs retain the genome of the donor, may regenerate indefinitely, and undergo differentiation into virtually any cell type of interest using a range of published protocols. There has been enormous interest among researchers regarding the application of iPSC technology to regenerative medicine and human disease modeling, in particular, modeling of neurologic diseases using patient-specific iPSCs. For instance, Parkinsons disease, Alzheimers disease, and spinal cord injuries may be treated with iPSC therapy or replacement tissues obtained from iPSCs. In this review, we discuss the work so far on generation and characterization of iPSCs and focus on recent advances in the use of human iPSCs in clinical setting.
Keywords: Cell-based therapy, Induced pluripotent stem cells, Precision medicine
Stem cells exhibit the capacity of self-renewal and may undergo differentiation into various tissue types. These are divided into pluripotent stem cells (PSCs; embryonic stem cells [ESCs] and induced pluripotent stem cells [iPSCs]) and multipotent stem cells (adult stem cells [ASCs]) based on their differentiation capacity [45]. PSCs, including ESCs derived from embryos and iPSCs derived by gene transfer, may undergo indefinite proliferation and differentiate into different types of tissues depending on the treatment conditions [86]. Multipotent stem cells, however, may be obtained from tissue-derived precursors (umbilical cord blood, bone marrow, adipose tissue, placenta, or blood), which are already grown tissues. Multipotent stem cells have only lineage-committed differentiation potential and may produce some cell types found within the particular tissue of origin () [27,45,86].
Isolation and characterization of pluripotent stem cells. ESC : embryonic stem cell, ICM : inner cell mass, iPSC : induced pluripotent stem cell, ASC : adult stem cell, CNS : central nervous system.
Of these stem cell types, iPSCs are derived from somatic cells by gene transfer in the presence of reprogramming factors. iPSCs face less ethical controversies than ESCs and are available for the development of new clinical applications and extending stem cell research to clinical setting [43,66,76,78]. Scientific investigations involving iPSCs in developmental biology, pharmaco-toxicology, and molecular biology have been accelerated by novel technologies aimed specifically to improve iPSC generation, growth, modif ication, and monitoring [3,10,74,77]. At present, PSCs research has rapidly evolved to offer the possibility of replacing regenerated and non-regenerated tissues, including the heart, pancreas, and brain, and provide various cell types [37,90,96,97]. In particular, the field of regenerative neuroscience is very active and has already reached a clinical trial stages [24,37,53,63,94]. The following sections discuss the main stem cell types and sources used in research and clinical trials along with their applications.
Human ESCs are self-renewing pluripotent cells, and may produce cells from the three germ layers. These cells are derived from the donated embryos either from in vitro fertilization procedure or created by somatic cell nuclear transfer technique (). ESCs or the cells of the embryo that have not undergone modification for less than 14 days are called omnipotent cells or pluripotent cells owing to their ability to differentiate into all cell and tissue types that make up the human body. In other words, these cells have the infinite ability to differentiate into all types of cells of the body [45,81,86].
Type of stem cells based on their differentiation capacities
Prior to 1998, scientists encountered difficulties in the isolation and cultivation of stem cells, as these cells present very short time during embryonic development and require special devices for their isolation from embryos. In 1998, however, a team of researchers led by Dr. James Thomson at the University of Wisconsin succeeded in isolating cells from the inner cell mass of blastocyst and cultivating human ESCs in a dish [81]. Therefore, ESCs have greatly contributed to developmental biology and medicine. For instance, ESCs have facilitated the development of insulin-producing cells to treat diabetes [96,98] or generation of neurons that can restore the function of patients paralyzed with spinal cord injuries [16,20]. Many groups have demonstrated successful transplantation, survival, and differentiation of ESCs into neural cells in rodent models [8,13,18,93]. In 2010, human ESC-derived oligodendrocyte progenitors were generated by Geron Corporation and a first-ever clinical trial involving patients with spinal cord injury (SCI) was performed [2,75]. Advanced Cell Technology also reported a clinical trial using human ESC-derived retinal pigment epithelium to treat dry age-related macular degeneration in 2012 [72]. Despite these advantages, embryonic cells obtained from the fusion of sperm and egg may cause severe immune rejection when used in patient with DNA from allogenic embryonic cells which was not autologus [5,12]. In addition, the use of human embryos may encounter ethical issues, which limit research and clinical applications. Therefore, it is necessary to develop new pluripotent cells that circumvent ethical or immunological problems [45,86].
ASCs are tissue-specific stem cells characterized with tissue-restricted differentiation. These cells have multipotency characteristics but lose pluripotency. ASCs are derived from the umbilical cord blood, bone marrow, adipose tissue, placenta, blood, or brain without direct use of embryo. These are primitive cells isolated just before undergoing differentiation into specific organs such as the bone, fat, cartilage, neuron, and blood. These include hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), and neural stem cells (NSCs), all of which have become an important source for regenerative medicine [27,45].
The umbilical cord blood and bone marrow contain large number of HSCs and MSCs, including stromal cells. Adipose tissue is a source of MSCs, which have the potential to differentiate into blood cells, bone, fat, and cartilage [17,30]. NSCs may be obtained from several regions of the fetal, postnatal, and adult central nervous system, including the subventricular zone of the brain and the spinal cord that may contain precursors for neurons, oligodendrocytes, and astrocytes [38,46,64].
ASCs have been extensively studied and are being tested in clinical trials for various diseases, including SCI [16,17,30]. One of the important functions of ASCs is their anti-inflammatory and immunomodulatory effects and their ability to secret several neurotrophic factors; hence, ASCs may provide trophic support for endogenous and co-implanted cells [7,14,15,47]. In addition, ASCs offer the advantage of avoiding less ethical debate than ESCs because these cells are isolated from the already-grown body tissues. However, ASCs tend to be difficult to proliferate and differentiate; hence, obtaining a desired cell shape or sufficient number of cells may be challenging [17,27,30].
iPSCs were first developed by Yamanaka in 2006 using mice [78]; human iPSCs were subsequently established in 2007 [76]. Since then, other researchers have developed human iPSCs and confirmed the reproducibility of the Yamanakas research technique, a globally approved technology [42,44,58,92]. iPSCs are derived from somatic cells of the adult body through the expression of specific exogenous genes or proteins and resemble ESCs morphologically, antigenically, and phenotypically in many ways. iPSCs have the following similarities as compared to ESCs derived from blastocysts [45,74,77,86] : 1) the shape of the cell (round shape, large nucleus, and phosphorus, little cytoplasm) and the speed of growth are similar. 2) Gene expression and chromatin modification patterns are similar. 3) It may form teratoma in immunodeficient mice. 4) It produces chimera mouse upon insertion into a mouse blastocyst. And 5) germ line transmission of genes is possible.
Unlike ESCs, iPSCs have been generated from the tissues with somatic cells, such as the skin, dental tissue, peripheral blood, and urine. Thus, generation of iPSCs showed less ethical problems than ESCs and offers the advantage of customized treatment using the somatic cells of the patient with characteristics same as ESCs [9,19,25,80,82,90].
Yamanakas team successfully induced pluripotency in adult somatic cells using four retrovirally transfected transcription factors, namely, Octamer 3/4 (Oct3/4), SRY-box containing gene 2 (Sox2), Krppel-like factor 4 (Klf4), and the protooncogene cytoplasmic Myc protein (c-Myc), in fibroblasts () [76,78]. However, the retroviral infection technology that delivers each of the Yamanaka factors (Oct3/4, Sox2, Klf4, and c-Myc; reprogramming factors; first generation method) has two disadvantages for clinical applications. First, genomic integration of reprogramming factors may lead to unwanted effects such as tumorigenesis [5,25,55]. Second, this technology may lead to impairment of pluripotency. Reprogramming factors are required to establish pluripotency, but continual activation of exogenous reprogramming factors may decrease the differentiation capacity into specific cell types or transform cells altogether [44,92].
Generation and applications of iPSCs from somatic cells. iPSCs can be applied in the field of clinical research for 1) patient-specific cell therapy, 2) drug screening, and 3) disease modeling. iPSC : induced pluripotent stem cell, Oct4 : octamer-binding transcription factor 4, Klf4 : Krppel-like factor 4, Sox2 : SRY-box containing gene 2, c-Myc : cytoplasmic Myc gene.
Therefore, alternative induction methods have been introduced to avoid direct alterations of host cell DNA. The pluripotency genes either remain separate from the host genome or may be completely removable [21,80]. For instance, to involve the transient expression of reprogramming factors or virus-free, using adenoviruses [99], plasmids [54], minicircle vectors [50], episomal vectors [61,91], Sendai viruses [29,87], synthetic mRNAs [84] or recombinant proteins [95] were developed (). iPSC reprogramming technology has been recently introduced to improve safety and increase efficiency through chemical approaches with small molecules [39,41]. This new generation protocol may help achieve more controllable reprogramming than that induced by transcription factors. These advancements have enabled the use of iPSCs for therapeutic purposes [9,40,43,63,90].
Safety of cell reprogramming technologies.
Many research groups have studied the differentiation potential of iPSCs into three germ layers in humans for clinical applications [3,11,37,90,96]. Human iPSCs use the same transcription network as ESCs, with similar early cell fate control mechanisms [45,86]. For clinical applications, many specific lineage-committed cell types are required for cell therapy; these may be generated through good manufacturing practice conditions [82]. The production of specific cell subtypes for therapy may necessitate specific culture conditions. These differences between the trophic responses in vitro and in vivo pose major challenges to the clinical translation of preclinical iPSC studies [43,66,74].
iPSCs may be used for the following applications : 1) development of disease-specific autologous cell therapy, 2) disease models to evaluate underlying mechanisms, and 3) drug screening and toxicity tests [33,43,53,66,74,97]. However, as the history of iPSC research is short, the studies must be adequately verified to confirm the safe application of these cells for cell therapy. In addition, human iPSCs derived from the somatic tissue of living donors and human tissue harvesting require extensive ethical and legal considerations regarding the dissemination of results and potential commercial benefit to donors for clinical translation [53,97]; hence, standard regulations and policies need to be established.
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