Edited by: Issam Lebbi, Alyssa Polyclinics for Woman, Mother and Child, Tunisia
Reviewed by: Anis Feki, Hôpitaux Fribourgeois, Switzerland; Diane De Neubourg, University Hospitals Leuven, Belgium
This article was submitted to Gynecology and Obstetrics, a section of the journal Frontiers in Surgery.
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Since 2006, several laboratories have proved that somatic cells can be reprogramed into induced pluripotent stem cells (iPSCs). iPSCs have enormous potential in stem cell biology as they can give rise to numerous cell lineages, including the three germ layers. In this review, we discuss past and recent advances in human iPSCs used for modeling diseases
By definition, stem cells can differentiate spontaneously into all cell types that form the human body. They have the ability to both differentiate into other mature cell types and maintain an undifferentiated state by self-renewal. These unique properties form the basis for stem cell use in cell and tissue regeneration. Currently, embryonic stem cells (ESCs) are the most widely studied stem cell type. ESCs arise from culture of primitive ectoderm cells of the inner cell mass of blastocysts and show pluripotency properties. Under strict culture conditions, they can perpetuate their undifferentiated pluripotent state indefinitely and are therefore an
The first iPSC lines were generated from adult fibroblasts by retrovirus-mediated introduction of four transcription factors into the genome of somatic cells (
We conducted an extensive Medline search using the following search terms: iPSCs and germ cell differentiation. A total of 5897 articles dating from 1967 to 2013 were initially retrieved. Since the topic is innovative, original articles of any design and review articles published in English and French were suitable for inclusion. Selection criteria were based on the main outcome of interest referenced in this baseline of articles, namely the potential in reproductive medicine of iPSCs reprogramed from animal and human somatic cells, including differentiation into germ lines and infertility modeling, with a view to synthesizing the state of current knowledge for clinical applicability in humans. Regarding issues connected to the main subject, namely use of iPSC line differentiation to (a) understand the physiopathology of diseases, (b) study the efficacy and toxicology of new medical therapy, and (c) regenerate cells and tissues, the goal was to introduce the reader to the literature, rather than provide an exhaustive review. The final number of studies referenced in this review is 135.
Since the creation of the first-line of iPSCs from mature adult cells by Takahashi and Yamanaka (
Reference | Cell source | Additional factors | Main evaluation | |
---|---|---|---|---|
( |
Fibroblast XY | Fetal gonadal cells | PGCs | Expression (STELLA, VASA, ACROSIN) |
Genomic imprint ( |
||||
( |
Fibroblast XY, XX | RA, forskolin, and CYP26 | PGCs spermatids | Expression (VASA, SYCP3) |
Genomic imprint ( |
||||
Genome ploidy | ||||
( |
Fibroblast XY, XX | BMP 4, 7, and 8 | Spermatids | Expression (VASA, ACROSIN) |
Genome ploidy | ||||
( |
Fibroblast XY, XX | Spermatids | Expression (VASA, ACROSIN) | |
Genomic imprint ( |
||||
Genome ploidy | ||||
( |
Fibroblast XX, XY, XXY | BMP 4, 7, and 8 | PGCs | XCI ( |
Transcriptome of differentially expressed X-linked genes | ||||
( |
Fibroblast XY | BMP 4, 7, and 8 | SSCs spermatocytes | Expression (VASA, ACROSIN) |
Spermatids | Genomic imprint ( |
|||
Genome ploidy |
Induced pluripotent stem cells technology provides a unique platform to identify possible therapeutic agents, evaluate their efficacy and toxicity, and study gene repair associated with cell replacement therapy. Indeed, derivation of patient-specific familial dysautonomia (FD) iPSCs (
Use of cardiomyocytes differentiated from human catecholaminergic polymorphic ventricular tachycardia (CPVT) iPSCs has provided insights into arrhythmia mechanisms in CPVT, a calcium-dependent familial arrhythmogenic disorder associated with dominant mutations in the cardiac ryanodine receptor gene, allowing screening of the effects of disease aggravators (adrenergic stimulation) and drug treatments (beta blockers and flecainide) (
These latter developments demonstrate the feasibility of using
Beyond
In humans, a number of clinical studies have already revealed the benefits of autologous non-iPSC transplantation, particularly for functional recovery (
There is no doubt that parenthood plays an important role in quality of life, so fertility preservation or restoration strategies need to be developed for infertile patients. Storage of spermatozoa, oocytes, or ovarian tissue should be the first-line treatment approach, as their reproductive potential after freezing has already been proven in humans. However, storage of mature or immature germ cells is not always possible, either because of lack of time in an emergency context like cancer therapy, or inaccessibility to the technique at the time of disease management. For these patients, generation of gametes from iPSCs would be an innovative strategy that could give them hope of becoming parents. Use of non-gametogenic pluripotent stem cells as a source of germ cells could also benefit patients suffering from congenital diseases affecting reproduction, such as Klinefelter syndrome, Y chromosome microdeletions, and Turner syndrome, who may have already lost their germ cells at the time of diagnosis. It could also be effective for patients whose germ cells are not functioning, for instance boys with cryptorchid testes.
During embryonic development, primordial germ cells (PGCs), differentiated from epiblast cells, are identifiable at 4 weeks of gestation and migrate through the epiblastic crest to colonize the gonadal ridges by 7 weeks of gestation (
Due to the complexity of gametogenesis
Spontaneous differentiation of iPSCs occurs after 4–7 days of culture and is highly variable and inconstant, resulting in different cell types from the three germ layers (endoderm, mesoderm, and ectoderm) in varying amounts. Several studies have reported derivation of germ cell precursors and gametes from mouse iPSCs. Injection of iPSCs into blastocysts generated chimeric pups, and analysis of host organs demonstrated the extensive contribution of injected iPSCs to various organs, including the eyes, ears, tail, claws, kidneys, liver, lungs, stomach, guts, and testes (
During spontaneous iPSC differentiation, a small population of male germ cells, including round spermatid-like cells, was observed (
So far, no mature sperm have been obtained
While numerous studies have demonstrated the ability of ESCs to differentiate into female germ cells, with some groups reporting formation of follicle-like structures and oocyte-like cells (
Since the discovery of PSCs in human beings, scientists have looked at the possibility of using this source of special cells to regenerate tissue and organs, with a considerably reduced risk of an immune response. Despite the great promise of iPSC technology, there are still barriers to overcome before these cells can be used in a clinical context.
The gold standard technique utilized to reprogram somatic cells is the inducible lentiviral vector that reaches 2% efficiency (
Induced pluripotent stem cell lines carry the risk of mutagenesis. Strategies to overcome this barrier and eventually offer the possibility of potential application in humans should be implemented. Excisable Lentiviral (
Finally, reprograming technology allows avoidance of the stem cell stage by direct reprograming, converting endogenous cells directly into desired cell types by gene transfer of defined factors, as has been demonstrated in hepatocyte (
Numerous pre-clinical trials (shown in Table
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Disease models | Reference | Somatic cell source | Physiopathological screening or drug testing |
---|---|---|---|
Lesch–Nyhan syndrome (carrier) | ( |
Fibroblast | N |
Gaucher’s disease, type III | ( |
Fibroblast | Y |
Type 1 diabetes | ( |
Fibroblast | N |
α1-Antitrypsin deficiency | ( |
Fibroblast | N |
( |
Fibroblast | N | |
Glycogen storage disease Ia | ( |
Fibroblast | N |
( |
Fibroblast | Y | |
Familial hypercholesterolemia | ( |
Fibroblast | N |
Crigler–Najjar syndrome | ( |
Fibroblast | N |
( |
Fibroblast | Y | |
Hereditary tyrosinemia, type 1 | ( |
Fibroblast | N |
( |
Fibroblast | Y | |
Hurler syndrome | ( |
Fibroblast | N |
Keratinocyte | |||
Mucopolysaccharidosis type IIIB | ( |
Fibroblast | Y |
Niemann-Pick type C1 | ( |
Fibroblast | N |
Parkinson’s disease | ( |
Fetal cortical progenitor | Y |
( |
Fibroblast | N | |
( |
Fibroblast | Y | |
( |
Fetal lung fibroblast | Y | |
Bone marrow mesenchymal stem cells | |||
( |
Fibroblast | Y | |
( |
Fibroblast | N | |
( |
Fibroblast | Y | |
Huntington’s disease | ( |
Fibroblast | N |
( |
Fibroblast | N | |
Familial amyotrophic lateral sclerosis | ( |
Fibroblast | N |
( |
Fibroblast | Y | |
Familial dysautonomia | ( |
Fibroblast | Y |
Rett syndrome | ( |
Fibroblast | Y |
( |
Fibroblast | N | |
( |
Fibroblast | N | |
Spinal muscular atrophy | ( |
Fibroblast | Y |
( |
Fibroblast | N | |
Angelman’s syndrome | ( |
Fibroblast | Y |
Prader–Willi syndrome | ( |
Fibroblast | N |
( |
Fibroblast | N | |
Friedriech’s ataxia | ( |
Fibroblast | N |
Schizophrenia | ( |
Fibroblast | Y |
Machado–Joseph disease | ( |
Fibroblast | Y |
Childhood cerebral Adrenoleukodystrophy and adrenomyeloneuropathy | ( |
Fibroblast | Y |
Alzheimer’s disease | ( |
Fibroblast | Y |
( |
Fibroblast | Y | |
Warkany syndrome 2 X-linked adrenoleukodystrophy | ( |
Fibroblast | Y |
( |
Amniocyte | Y | |
Fibroblast | |||
Emanuel syndrome | ( |
Amniocyte | N |
Fibroblast | |||
Gyrate atrophy | ( |
Fibroblast | Y |
Retinitis pigmentosa | ( |
Fibroblast | N |
( |
Fibroblast | Y | |
( |
Fibroblast | Y | |
Leber’s congenital amaurosis | ( |
Fibroblast | N |
Usher syndrome | N | ||
Leber’s hereditary optic neuropathy | N | ||
Fanconi’s anemia | ( |
Fibroblast | N |
β-Thalassemia | ( |
Fibroblast | N |
Polycythemia vera | ( |
CD34+ cell | N |
Primary myelofibrosis | ( |
N | |
Sickle-cell anemia | ( |
Fibroblast | N |
Scleroderma | Fibroblast | N | |
Chronic myeloid leukemia disease | ( |
Fibroblast | N |
( |
CD34+ cell | N | |
Severe congenital neutropenia | ( |
Fibroblast | N |
LEOPARD syndrome | ( |
Fibroblast | N |
Long-QT 1 | ( |
Fibroblast | N |
Timothy syndrome | ( |
Fibroblast | Y |
Overlapping Na+ channel disease syndrome | ( |
Fibroblast | N |
Familial dilated cardiomyopathy | ( |
Fibroblast | Y |
Long-QT 2 | ( |
Fibroblast | Y |
( |
Fibroblast | Y | |
( |
Fibroblast | Y | |
Catecholaminergic polymorphic ventricular tachycardia | ( |
Fibroblast | Y |
( |
Fibroblast | Y | |
( |
Fibroblast | Y | |
( |
Fibroblast | Y | |
( |
Fibroblast | Y | |
Arrhythmogenic right ventricular cardiomyopathy | ( |
Fibroblast | N |
( |
Fibroblast | Y | |
Down syndrome | ( |
Fibroblast | N |
Cystic fibrosis | ( |
Fibroblast | N |
Recessive dystrophic epidermolysis bullosa | ( |
Fibroblast | N |
Keratinocyte | |||
Patau syndrome | ( |
Amniocyte | Y |
Fibroblast | |||
Klinefelter syndrome | ( |
Fibroblast | N |
The authors thank Mira Hryniuk, B.A., for reviewing the English language of this manuscript.