Totipotent cells can form all the cell types in a body, plus the extraembryonic, or placental, cells. Embryonic cells within the first couple of cell divisions after. Induced pluripotent stem cells have recently acquired particular E-mail: [email protected] Received date: December 03, ; Accepted date: December 31, stem cells can generally be classified into totipotent, multipotent and Also, a long list of agents or vectors have been used in iPSC. So dorms lamech outside or they'll gaze on the bathroom. totipotent vs pluripotent yahoo dating totipotent vs pluripotent yahoo dating top online dating sites.
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The expression of SSEA5 is relatively specific for human ESC but the other surface marker is expressed in differentiated tissues [ 39 ], so the antibody-selection of ESCs could be limited by the specificity of the expression of their specific surface markers. There is another limitation for the antibody based strategies and the problem is that some progenitor cells could dedifferentiate into pluripotent cells after transplantation and leading to teratoma formation [ 40 ].
It has been reported that natural killer cells are not important for the rejection of human PSCs in vivo [ 41 ]; however, in addition to antibody based strategies there are reports on the complement dependent control of teratoma formation that involves the innate immunity. In Koch et al. Recently it was demonstrated that an antibody against Claudin-6 a cytotoxinconjugated antibody that targets undifferentiated cells; and Clostridium perfringens enterotoxin, a toxin that binds several Claudins efficiently kills undifferentiated cells, thus eliminating the tumorigenic potential and teratoma formation of human pluripotent stem cell-containing cultures [ 44 ].
Small molecules for Preventing Teratoma Small molecule targeting of pluripotent stem cell specific antiapoptotic factors is an effective strategy to eliminate the risk of teratomas occurrence in pluripotent stem cell-based therapy. In , Bieberich and colleagues reported the selective apoptosis of pluripotent stem cells by novel ceramide analogue that prevents teratoma formation. They were reported that undifferentiated ESCs could be eliminated from cultures of ESC-derived neuronal cells by treatment with ceramide analogue N-oleoyl serinol [ 45 ].
Increased level of ceramide is a part of a mechanism that promotes programmed cell death during the development of the mouse brain. The addition of ceramide analogues to mouse ESCs eliminates the undifferentiated cells, but leaves those that have differentiated without any cytotoxic effect [ 46 ]. In a study concerning teratoma formation, the levels of a growth factor from the EGF-CFC family Cripto were down regulated by generating a Cripto knock-out mouse. Cripto is over-expressed in a wide range of epithelial cancers [ 47 ] and its repression enhances neuronal differentiation.
When Cripto knock-out ESCs were grown in the presence of FGF-8, and after grafting to immunosuppressed hemiparkinsonian rats, the Cripto negative ESC-derived grafts contained large numbers of dopaminergicpositive neurons without any teratomas [ 48 ].
In , researchers in Korea found that quercetin and YMinduced selective cell death is enough to inhibit teratoma formation after transplantation of human pluripotent stem cell-derived cells [ 49 ]. YM is an antagonist for surviving effect in pluripotent cells and quercetin QC , a dietary flavonoid, is widely found in fruits like apple , vegetables and green tea.
QC has the ability to suppress various types of cancer cells and tumor growth, which are related, to expression of surviving [ 50 ]. PSCs are likely critically dependent, for their survival and self-renewal, on relatively few anti-apoptotic genes like Bcl10 and survivin that are highly expressed in ESCs. QC treatment does not seem to influence the differentiation of PSCs into three germ layer lineages [ 49 ]. FTY the pro-drug analogue for sphingosinephosphate is already used in clinical trials to treat multiple sclerosis, mainly because of its immunosuppressing activity Davis et al.
The experiments showed that FTY eliminates teratoma-forming cells and protects neural progenitor cells from N-oleoyl serinol-inducible apoptosis [ 51 ]. It has been shown that encapsulation of ESC with membranes 2. Also it has been reported the mouse ESCs but not the human ESCs formed aggregates within the alginate capsules, which remained free of fibrosis [ 52 ]. These genes that related to the pluripotency are linked to stem cell tumorigenesis [ 6 ].
It was reported that gancyclovir treatment could prevent the teratoma formation of ESCs with a transgenic thymidine kinase gene driven by a mouse Nanog promoter [ 53 ], however the random integration of the transgene in the genome could change the promoter activity and increase the risk of cancer. In , Rong et al. They chose the pluripotency gene Nanog locus that is specifically expressed in pluripotent cells.
The Nanog is rapidly down-regulated post-epiblast stage during embryonic development [ 55 ]. Inhibition of Pin1 activity and destroying the Pin1— Nanog interaction in ESCs suppresses their capability to self-renew and to form teratomas [ 56 ]. Cell Signaling and Teratoma Previously it was thought that the pluripotent marker Oct-4 is enough to predict the formation of teratomas and the removal of Octpositive cells could prevent teratomas from developing after transplantation [ 57 ].
But we know that the Oct-4 negative stem cells could contribute to the teratoma formation. Some growth factors also influence apoptosis via PKC, PI3K Phosphatidyl- Inositol kinase , and Akt pathways [ 62 ] and the decrease in the levels of these factors could initiate teratoma formation and enhance its size and incidence. The cyclin dependent kinase CDK inhibitor, p18INK4c, is a known tumor suppressor that can inhibit self-renewal of tumor cells or adult stem cells [ 63 ].
Also experiments have been shown that the teratoma volume from poverexpressing ESCs was found to be significantly reduced compared to the control group [ 64 ]. So, p18 inhibits teratoma growth, which is consistent with a role for p18 as a tumor suppressor in somatic tissues [ 65 ]. The B-cell lymphoma 2 Bcl-2 families, consisting more than 25 pro- and anti-apoptotic members, regulates the caspase cascade and apoptosis [ 66 ].
These proteins maintain a balance between new cells and old one. ESCs over-expressing Bcl-2 proliferate in feeder-free cultures when supplemented with leukemia inhibitory factor LIF [ 67 ], indicating that attenuation of apoptosis is critical for ESCs survival and self-renewal.
The teratomas generated from Bcl-2 over-expressing cells are significantly larger than control cells, suggesting that Bcl enhances ESCs survival and teratoma formation in vivo [ 68 ].
Some studies demonstrated that a distinct mitochondrial p53 function regulates apoptotic signals in ESCs [ 69 , 70 ]. These results provide a proof of principle that ZFNs can be used to produce gene-corrected human iPSCs that could be used for therapeutic applications indicating that ZFN technology can be used to correct a disease-causing mutation by HR [ 47 ].
There are 2 humanized mouse models of SCD: The 2 humanized mouse models have proven valuable in studying disease mechanisms and testing therapeutic strategies such as gene therapy [ 2 ]. Results of the study showed that engrafted mice revealed mature lymphoid cells [ 2 ]. In , a similar experiment was performed using the Townes humanized SCD mouse model.
Autologous ESCs were genetically corrected by HR, differentiated toward the hematopoietic lineage and transplanted into the Townes mice. Mouse and human fibroblasts can be programmed into an embryonic stem cell -like state by introducing combinations of 4 transcription factors. However, the therapeutic potential of such iPSCs remained undefined [ 48 ]. By using a humanized SCD mouse model, it was shown that mice can be rescued after transplantation of hematopoietic progenitors obtained in vitro from autologous iPSCs.
This was achieved after correction of the human sickle Hb allele by gene-specific targeting. These results provided proof of principle that transcription factor-induced reprogramming combined with gene and cell therapy can be employed for treatment of the disease in mice [ 48 ].
However, the problems associated with using retroviruses and oncogenes for reprogramming need to be resolved before considering iPSCs for human therapy [ 48 ].
Although reprogramming of human somatic cells into iPSCs has been achieved, future therapeutic application of iPSCs in humans requires overcoming the following obstacles: Current advances in molecular reprogramming set the stage for devising alternative strategies such as: The results impressively demonstrated the potential for harnessing personalized stem cells for the treatment and potential cure of SCD [ 2 ]. The peripheral blood of engrafted mice showed remarkable restoration of normal erythroid indices and compelling evidence for the potential therapeutic use of iPSCs in hemoglobinopathies [ 2 ].
However, neither of the reports differentiated the cells and functionally tested them to show sickling or a reduction in sickling after correction [ 2 ].
Human iPSCs are capable of: Since iPSCs can proliferate indefinitely and can be selected for a phenotype of interest, they are potential candidates to organize complementary sources of RBCs for transfusion.
Before use in clinical practice, the procedures need to be optimized [ 49 ]. The crucial points that remain to be resolved are optimization of erythroid proliferation and differentiation, and definition of good manufacturing practice conditions for industrial production [ 49 ].
Genetic correction of iPSCs was made by a novel in vitro neutrophil differentiation system. The study resulted in improvement of defective granulopoiesis [ 50 ]. CAMT is caused by loss of thrombopoietin-related MPLmediated signaling which induces severe pancytopenia leading to bone marrow failure with the onset of thrombocytopenia and anemia prior to leucopenia [ 51 ]. Myelofibrosis Recently, iPSCs were successfully generated from patients with: These disease specific iPSCs provide a research tool for studying the disease and potentially providing targeted therapy ultimately [ 52 ].
These iPSCs displayed severe reduction in hematopoietic differentiation potential and absent clonogenic capacity [ 53 ]. Familial platelet disorder FPD is an autosomal dominant disease of hematopoietic system that is caused by heterogenous mutations in RUNX1 [ 54 , 55 ]. After correction of RUNX1 mutation, megakaryopoiesis was restored [ 55 ]. These FPD-iPSCs were shown to be uniformly defective in emergence of hematopoietic progenitor cells and megakaryocytic differentiation. These results provide a rationale for a potential targeted therapy for JMML [ 56 ].
These leukemiaoriginating stem cells are critical for the initiation and maintenance of leukemias [ 59 ]. However, the existence of a similar cell population that may generate B-cell lymphocytic malignancies remains uncertain [ 59 ].
Detailed selection and molecular characterization of the specific cells of origin of each B-cell lymphoma entity are essential steps to better understanding of lymphomagenesis and to develop effective and potentially curative therapeutic modalities [ 59 ]. Solid tumors iPSCs have also been generated from malignant cells belonging to patients with gastrointestinal cancers [ 8 ]. Antitumor immunotherapy using T cell and natural killer NK cell-based therapies has demonstrated promising therapeutic potentials in patients with renal cell carcinoma, malignant melanoma and chemotherapy refractory AML [ 60 ].
The ability to modify human ESC and iPSC-derived NK cells with tumor-specific receptors may be utilized against a wide range of malignancies in the near future after having the appropriate pre-clinical and clinical trials performed [ 60 ]. Cancer-derived iPSCs are expected to provide a novel experimental opportunity to establish disease models [ 61 ]. These HSCs can practically be used in the treatment of hematological disorders including bone marrow failure syndromes and immunological disorders such as X-linked severe combined immunodeficiency with risks of graft rejection or graft versus host disease [ 62 ].
Banking of iPSCs Blood transfusion is a common procedure in modern medicine and it is being practiced throughout the world. However, blood supply is usually strained during natural disasters and wars [ 63 ]. Alternative substitutes such as synthetic oxygen radical carriers have been proven to be unsuccessful [ 63 ]. The main obstacle in organ and tissue transplantation is rejection by the recipient due to the 3 main immunological barriers: The problem of rejection in transplantation can be circumvented by using autologous stem cells such as iPSCs derived directly from the patient as these cells have the advantage of theoretical absence of immune rejection by the recipient [ 66 ].
Establishment of stem cell banks comprising HLA-typed human ESCs and iPSCs is a strategy that is proposed to overcome the immunological barriers of transplantation by providing HLA-matched tissues for the target population [ 67 ].
Tissues or organs derived from human PSCs could be the best solution to cure several human diseases that do not respond to standard therapies [ 65 ]. However, iPSCs have certain limitations, particularly the disease of the recipient and the possible difficulties in generation, expansion and manipulation of autologous preparations of iPSCs [ 66 ].
An alternative to using autologous iPSCs in the establishment of banks of well-characterized human adult cells that could be used to generate iPSCs and their derivatives has recently emerged [ 66 ].
However, current initiatives to establish banks for human iPSCs face real challenges in recruiting large numbers of donors with diverse diseases as well as genetic and phenotypic representations [ 69 ]. Also, reaching standards of good clinical manufacturing practices and quality controlled stem cell lines could be challenging [ 65 , 70 ]. A recent study showed that singledrop volumes of finger-prick blood samples are sufficient to perform cellular reprogramming, DNA sequencing and blood serotyping in parallel.
This novel strategy has the potential to facilitate development of large-scale human iPSC banking worldwide [ 69 ]. Additionally, a consortium of 26 partners has been formed to establish a European bank for iPSCs that will act as a central storage and distribution facility for human iPSCs to be used by researchers in order to study intractable disease and to develop new therapeutic strategies [ 71 ].
The discovery of deriving iPSCs from cord blood combined with the presence of non-hematopoietic stem and progenitor cells in cord blood may lead to enhanced therapeutic applications of these cells as well as enhanced use of cord blood banking [ 72 ].
The genetic diversity related to ancestry backgrounds of populations living in certain communities is another limitation for the establishment of iPSC banks [ 73 ]. However, a recent study performed in USA suggested that establishment of multiethnic haplobank of iPSC lines is a possible solution, but this can only be achieved by a large scale concerted worldwide collaboration [ 73 ].
Imaging of iPSCs Tracking iPSCs and investigating the feasibility of their utilization require the development of novel technology to monitor their location, proliferation, integration and differentiation in human recipients [ 74 ]. The ideal imaging technique should be non-toxic, biocompatible and highly specific. Plenty of progress has been achieved in this field and hopefully this will become a reality in clinical practice in the near future [ 74 ].
Ethical Issues Related to the Use of PSCs Regenerative medicine, which is currently on the stage of research, implies important ethical, legal and social issues that need to be addressed [ 75 ]. In our experiment, clusters of iPS cell-derived hepatocytes attached to the exterior surface of hollow fibers Figure 2C.
These cells survived at least 7 days after injection into the cartridge and showed hepatocyte-specific metabolic activity, such as albumin production and urea synthesis [ 19 ]. A schematic diagram of a BAL device. An example of a hollow-fiber type BAL device is illustrated.
Hepatocytes are embedded into the extracapillary space of the cartridge. Blood in vivo model or medium in vitro model flows into the lumen of the hollow fibers. Scanning electron microscopy images. Hollow fibers have numerous micropores that enable mass transfer between the lumen and the extracapillary space A,B. Hollow fibers play a role as a scaffold for embedded hepatocytes as well. A cluster of iPS cell-derived hepatocytes attaching to the exterior surface of hollow fibers is shown C.
It is well known that isolated hepatocytes do not proliferate in vitro. Furthermore, hepatocytes gradually lose their metabolic function with time in vitro, even with sophisticated tissue culture media [ 6 , 23 ].
Consequently, the limited supply of primary hepatocytes remains a major hindrance to successful use of BAL. In contrast, iPS cells, as well as embryonic stem ES cells, have the ability of infinite proliferation and self-renewal. Expansion and differentiation of iPS cells enables a continuous supply of large quantities of functional hepatocytes. Tolerance to the host immune system is another advantage of iPS cells. Immunological tolerance is a unique aspect of iPS cells, not shared by any other types of cells.
As described above, primary human hepatocytes, human hepatoblastoma cell line and cryopreserved porcine hepatocytes, have been explored for BAL use [ 1 - 13 ]. In these models, death of allogenic hepatocytes or xenogenic hepatocytes has arisen from immune-mediated cytotoxicity.
For example, Nyberg et al. Immunostaining revealed the deposition of canine IgG, canine IgM, and canine complement on the dead porcine hepatocytes. Similar results have been reported by other researchers [ 25 , 26 ], suggesting the likelihood of humoral immunity-mediated damage, involving immunoglobulins and complements of the host. Selectivity of mass transfer is mostly influenced by the pore size of the BAL membrane [ 24 , 27 ].
- Review summary
Stem Cell Transl Med 3: Hemoglobinopathies Attempts to cure thalassemia and SCD using gene therapy have been hampered by the large globin gene and globin promoters that are difficult to accumulate within vector systems [ 38 ].
Induced Pluripotent Stem Cells and Their Future Therapeutic Applications in Hematology