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Vasiliy Galat - One of the best experts on this subject based on the ideXlab platform.

  • application of small molecule chir99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of human Pluripotent Stem Cells
    Experimental Hematology, 2018
    Co-Authors: Yekaterina Galat, Dimantha Katukurundage, Irina Elcheva, Svetlana Dambaeva, Philip M Iannaccone, Kenneth D Beaman, Vasiliy Galat
    Abstract:

    Improving our understanding of the intricacies of hematopoietic specification of induced or embryonic human Pluripotent Stem Cells is beneficial for many areas of research and translational medicine. Currently, it is not clear whether, during human Pluripotent Stem Cells hematopoietic differentiation in vitro, the maturation of definitive progenitors proceeds through a primitive progenitor (hemangioblast) intermediate or if it develops independently. The objective of this study was to investigate the early stages of hematopoietic specification of Pluripotent Stem Cells in vitro. By implementing an adherent culture, serum-free differentiation syStem that utilizes a small molecule, CHIR99021, to induce human Pluripotent Stem Cells toward various hematopoietic lineages, we established that, compared with the OP9 coculture hematopoietic induction syStem, the application of CHIR99021 alters the early steps of hematopoiesis such as hemangioblasts, angiogenic hematopoietic progenitors, and hemogenic endothelium. Importantly, it is associated with the loss of hemangioblast progenitors, loss of CD43+ (primitive hematopoietic marker) expression, and predominant development of blast-forming unit erythroid colonies in semisolid medium. These data support the hypothesis that the divergence of primitive and definitive programs during human Pluripotent Stem Cells differentiation precedes the hemangioblast stage. Furthermore, we have shown that the inhibition of primitive hematopoiesis is associated with an increase in hematopoietic potential, which is a fruitful finding due to the growing need for lymphoid and myeloid Cells in translational applications.

  • cytokine free directed differentiation of human Pluripotent Stem Cells efficiently produces hemogenic endothelium with lymphoid potential
    Stem Cell Research & Therapy, 2017
    Co-Authors: Yekaterina Galat, Irina Elcheva, Svetlana Dambaeva, Philip M Iannaccone, Kenneth D Beaman, Aaruni Khanolkar, Vasiliy Galat
    Abstract:

    Background The robust generation of human hematopoietic progenitor Cells from induced or embryonic Pluripotent Stem Cells would be beneficial for multiple areas of research, including mechanistic studies of hematopoiesis, the development of cellular therapies for autoimmune diseases, induced transplant tolerance, anticancer immunotherapies, disease modeling, and drug/toxicity screening. Over the past years, significant progress has been made in identifying effective protocols for hematopoietic differentiation from Pluripotent Stem Cells and understanding stages of mesodermal, endothelial, and hematopoietic specification. Thus, it has been shown that variations in cytokine and inhibitory molecule treatments in the first few days of hematopoietic differentiation define primitive versus definitive potential of produced hematopoietic progenitor Cells. The majority of current feeder-free, defined syStems for hematopoietic induction from Pluripotent Stem Cells include prolonged incubations with various cytokines that make the differentiation process complex and time consuming. We established that the application of Wnt agonist CHIR99021 efficiently promotes differentiation of human Pluripotent Stem Cells in the absence of any hematopoietic cytokines to the stage of hemogenic endothelium capable of definitive hematopoiesis.

  • cytokine free directed differentiation of human Pluripotent Stem Cells efficiently produces hemogenic endothelium with lymphoid potential
    Stem Cell Research & Therapy, 2017
    Co-Authors: Yekaterina Galat, Irina Elcheva, Svetlana Dambaeva, Philip M Iannaccone, Kenneth D Beaman, Aaruni Khanolkar, Vasiliy Galat
    Abstract:

    The robust generation of human hematopoietic progenitor Cells from induced or embryonic Pluripotent Stem Cells would be beneficial for multiple areas of research, including mechanistic studies of hematopoiesis, the development of cellular therapies for autoimmune diseases, induced transplant tolerance, anticancer immunotherapies, disease modeling, and drug/toxicity screening. Over the past years, significant progress has been made in identifying effective protocols for hematopoietic differentiation from Pluripotent Stem Cells and understanding stages of mesodermal, endothelial, and hematopoietic specification. Thus, it has been shown that variations in cytokine and inhibitory molecule treatments in the first few days of hematopoietic differentiation define primitive versus definitive potential of produced hematopoietic progenitor Cells. The majority of current feeder-free, defined syStems for hematopoietic induction from Pluripotent Stem Cells include prolonged incubations with various cytokines that make the differentiation process complex and time consuming. We established that the application of Wnt agonist CHIR99021 efficiently promotes differentiation of human Pluripotent Stem Cells in the absence of any hematopoietic cytokines to the stage of hemogenic endothelium capable of definitive hematopoiesis. The hemogenic endothelium differentiation was accomplished in an adherent, serum-free culture syStem by applying CHIR99021. Hemogenic endothelium progenitor Cells were isolated on day 5 of differentiation and evaluated for their endothelial, myeloid, and lymphoid potential. Monolayer induction based on GSK3 inhibition, described here, yielded a large number of CD31+CD34+ hemogenic endothelium Cells. When isolated and propagated in adherent conditions, these progenitors gave rise to mature endothelium. When further cocultured with OP9 mouse stromal Cells, these progenitors gave rise to various Cells of myeloid lineages as well as natural killer lymphoid, T-lymphoid, and B-lymphoid Cells. The results of this study substantiate a method that significantly reduces the complexity of current protocols for hematopoietic induction, offers a defined syStem to study the factors that affect the early stages of hematopoiesis, and provides a new route of lymphoid and myeloid cell derivation from human Pluripotent Stem Cells, thus enhancing their use in translational medicine.

Irina Elcheva - One of the best experts on this subject based on the ideXlab platform.

  • application of small molecule chir99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of human Pluripotent Stem Cells
    Experimental Hematology, 2018
    Co-Authors: Yekaterina Galat, Dimantha Katukurundage, Irina Elcheva, Svetlana Dambaeva, Philip M Iannaccone, Kenneth D Beaman, Vasiliy Galat
    Abstract:

    Improving our understanding of the intricacies of hematopoietic specification of induced or embryonic human Pluripotent Stem Cells is beneficial for many areas of research and translational medicine. Currently, it is not clear whether, during human Pluripotent Stem Cells hematopoietic differentiation in vitro, the maturation of definitive progenitors proceeds through a primitive progenitor (hemangioblast) intermediate or if it develops independently. The objective of this study was to investigate the early stages of hematopoietic specification of Pluripotent Stem Cells in vitro. By implementing an adherent culture, serum-free differentiation syStem that utilizes a small molecule, CHIR99021, to induce human Pluripotent Stem Cells toward various hematopoietic lineages, we established that, compared with the OP9 coculture hematopoietic induction syStem, the application of CHIR99021 alters the early steps of hematopoiesis such as hemangioblasts, angiogenic hematopoietic progenitors, and hemogenic endothelium. Importantly, it is associated with the loss of hemangioblast progenitors, loss of CD43+ (primitive hematopoietic marker) expression, and predominant development of blast-forming unit erythroid colonies in semisolid medium. These data support the hypothesis that the divergence of primitive and definitive programs during human Pluripotent Stem Cells differentiation precedes the hemangioblast stage. Furthermore, we have shown that the inhibition of primitive hematopoiesis is associated with an increase in hematopoietic potential, which is a fruitful finding due to the growing need for lymphoid and myeloid Cells in translational applications.

  • cytokine free directed differentiation of human Pluripotent Stem Cells efficiently produces hemogenic endothelium with lymphoid potential
    Stem Cell Research & Therapy, 2017
    Co-Authors: Yekaterina Galat, Irina Elcheva, Svetlana Dambaeva, Philip M Iannaccone, Kenneth D Beaman, Aaruni Khanolkar, Vasiliy Galat
    Abstract:

    Background The robust generation of human hematopoietic progenitor Cells from induced or embryonic Pluripotent Stem Cells would be beneficial for multiple areas of research, including mechanistic studies of hematopoiesis, the development of cellular therapies for autoimmune diseases, induced transplant tolerance, anticancer immunotherapies, disease modeling, and drug/toxicity screening. Over the past years, significant progress has been made in identifying effective protocols for hematopoietic differentiation from Pluripotent Stem Cells and understanding stages of mesodermal, endothelial, and hematopoietic specification. Thus, it has been shown that variations in cytokine and inhibitory molecule treatments in the first few days of hematopoietic differentiation define primitive versus definitive potential of produced hematopoietic progenitor Cells. The majority of current feeder-free, defined syStems for hematopoietic induction from Pluripotent Stem Cells include prolonged incubations with various cytokines that make the differentiation process complex and time consuming. We established that the application of Wnt agonist CHIR99021 efficiently promotes differentiation of human Pluripotent Stem Cells in the absence of any hematopoietic cytokines to the stage of hemogenic endothelium capable of definitive hematopoiesis.

  • cytokine free directed differentiation of human Pluripotent Stem Cells efficiently produces hemogenic endothelium with lymphoid potential
    Stem Cell Research & Therapy, 2017
    Co-Authors: Yekaterina Galat, Irina Elcheva, Svetlana Dambaeva, Philip M Iannaccone, Kenneth D Beaman, Aaruni Khanolkar, Vasiliy Galat
    Abstract:

    The robust generation of human hematopoietic progenitor Cells from induced or embryonic Pluripotent Stem Cells would be beneficial for multiple areas of research, including mechanistic studies of hematopoiesis, the development of cellular therapies for autoimmune diseases, induced transplant tolerance, anticancer immunotherapies, disease modeling, and drug/toxicity screening. Over the past years, significant progress has been made in identifying effective protocols for hematopoietic differentiation from Pluripotent Stem Cells and understanding stages of mesodermal, endothelial, and hematopoietic specification. Thus, it has been shown that variations in cytokine and inhibitory molecule treatments in the first few days of hematopoietic differentiation define primitive versus definitive potential of produced hematopoietic progenitor Cells. The majority of current feeder-free, defined syStems for hematopoietic induction from Pluripotent Stem Cells include prolonged incubations with various cytokines that make the differentiation process complex and time consuming. We established that the application of Wnt agonist CHIR99021 efficiently promotes differentiation of human Pluripotent Stem Cells in the absence of any hematopoietic cytokines to the stage of hemogenic endothelium capable of definitive hematopoiesis. The hemogenic endothelium differentiation was accomplished in an adherent, serum-free culture syStem by applying CHIR99021. Hemogenic endothelium progenitor Cells were isolated on day 5 of differentiation and evaluated for their endothelial, myeloid, and lymphoid potential. Monolayer induction based on GSK3 inhibition, described here, yielded a large number of CD31+CD34+ hemogenic endothelium Cells. When isolated and propagated in adherent conditions, these progenitors gave rise to mature endothelium. When further cocultured with OP9 mouse stromal Cells, these progenitors gave rise to various Cells of myeloid lineages as well as natural killer lymphoid, T-lymphoid, and B-lymphoid Cells. The results of this study substantiate a method that significantly reduces the complexity of current protocols for hematopoietic induction, offers a defined syStem to study the factors that affect the early stages of hematopoiesis, and provides a new route of lymphoid and myeloid cell derivation from human Pluripotent Stem Cells, thus enhancing their use in translational medicine.

Ludovic Vallier - One of the best experts on this subject based on the ideXlab platform.

  • cell cycle regulators control mesoderm specification in human Pluripotent Stem Cells
    Journal of Biological Chemistry, 2019
    Co-Authors: Loukia Yiangou, Daniel Ortmann, Rodrigo A Grandy, Sanjay Sinha, Anna Osnato, Ludovic Vallier
    Abstract:

    The mesoderm is one of the three germ layers produced during gastrulation from which muscle, bones, kidneys, and the cardiovascular syStem originate. Understanding the mechanisms that control mesoderm specification could inform many applications, including the development of regenerative medicine therapies to manage diseases affecting these tissues. Here, we used human Pluripotent Stem Cells to investigate the role of cell cycle in mesoderm formation. To this end, using small molecules or conditional gene knockdown, we inhibited proteins controlling G1 and G2/M cell cycle phases during the differentiation of human Pluripotent Stem Cells into lateral plate, cardiac, and presomitic mesoderm. These loss-of-function experiments revealed that regulators of the G1 phase, such as cyclin-dependent kinases and pRb (retinoblastoma protein), are necessary for efficient mesoderm formation in a context-dependent manner. Further investigations disclosed that inhibition of the G2/M regulator cyclin-dependent kinase 1 decreases BMP (bone morphogenetic protein) signaling activity specifically during lateral plate mesoderm formation while reducing fibroblast growth factor/extracellular signaling-regulated kinase 1/2 activity in all mesoderm subtypes. Taken together, our findings reveal that cell cycle regulators direct mesoderm formation by controlling the activity of key developmental pathways.

  • generation of hepatocytes from Pluripotent Stem Cells for drug screening and developmental modeling
    Methods of Molecular Biology, 2015
    Co-Authors: Richard L Gieseck, Ludovic Vallier, Nicholas R F Hannan
    Abstract:

    Hepatocytes produced from the differentiation of human Pluripotent Stem Cells can be used to study human development and liver disease, to investigate the toxicological response of novel drug candidates, and as an alternative source of primary Cells for transplantation therapies. Here, we describe a method to produce hepatocytes by differentiating human Pluripotent Stem Cells into definitive endoderm, patterning definitive endoderm into anterior definitive endoderm, specifying anterior definitive endoderm into hepatic endoderm, and differentiating hepatic endoderm into immature hepatocytes. These Cells are further matured in either two-dimensional or three-dimensional culture conditions to produce Cells capable of metabolizing xenobiotics and generating liver-specific proteins, such as albumin and alpha 1 antitrypsin.

  • generation of human induced Pluripotent Stem Cells from peripheral blood mononuclear Cells using sendai virus
    Methods of Molecular Biology, 2015
    Co-Authors: Filipa A C Soares, Ludovic Vallier, Roger A Pedersen
    Abstract:

    This protocol describes the efficient isolation of peripheral blood mononuclear Cells from circulating blood via density gradient centrifugation and subsequent generation of integration-free human induced Pluripotent Stem Cells. Peripheral blood mononuclear Cells are cultured for 9 days to allow expansion of the erythroblast population. The erythroblasts are then used to derive human induced Pluripotent Stem Cells using Sendai viral vectors, each expressing one of the four reprogramming factors Oct4, Sox2, Klf4, and c-Myc.

  • production of hepatocyte like Cells from human Pluripotent Stem Cells
    Nature Protocols, 2013
    Co-Authors: Nicholas R F Hannan, Ludovic Vallier, Charispatricia Segeritz, Thomas Touboul
    Abstract:

    Large-scale production of hepatocytes from a variety of genetic backgrounds would be beneficial for drug screening and to provide a source of Cells to be used as a substitute for liver transplantation. However, fully functional primary hepatocytes remain difficult to expand in vitro, and circumventing this problem by using an alternative source of Cells is desirable. Here we describe a 25-d protocol to direct the differentiation of human Pluripotent Stem Cells into a near-homogenous population of hepatocyte-like Cells. As Cells progress through this protocol, they express genes in a chronological manner similar to that described during in vivo hepatic development. The protocol relies on culture syStems devoid of serum, feeders or complex extracellular matrices, which enable molecular analyses without interference from unknown factors. This approach works efficiently with human embryonic Stem Cells and human induced Pluripotent Stem Cells and was recently used to model liver diseases in vitro.

Yekaterina Galat - One of the best experts on this subject based on the ideXlab platform.

  • application of small molecule chir99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of human Pluripotent Stem Cells
    Experimental Hematology, 2018
    Co-Authors: Yekaterina Galat, Dimantha Katukurundage, Irina Elcheva, Svetlana Dambaeva, Philip M Iannaccone, Kenneth D Beaman, Vasiliy Galat
    Abstract:

    Improving our understanding of the intricacies of hematopoietic specification of induced or embryonic human Pluripotent Stem Cells is beneficial for many areas of research and translational medicine. Currently, it is not clear whether, during human Pluripotent Stem Cells hematopoietic differentiation in vitro, the maturation of definitive progenitors proceeds through a primitive progenitor (hemangioblast) intermediate or if it develops independently. The objective of this study was to investigate the early stages of hematopoietic specification of Pluripotent Stem Cells in vitro. By implementing an adherent culture, serum-free differentiation syStem that utilizes a small molecule, CHIR99021, to induce human Pluripotent Stem Cells toward various hematopoietic lineages, we established that, compared with the OP9 coculture hematopoietic induction syStem, the application of CHIR99021 alters the early steps of hematopoiesis such as hemangioblasts, angiogenic hematopoietic progenitors, and hemogenic endothelium. Importantly, it is associated with the loss of hemangioblast progenitors, loss of CD43+ (primitive hematopoietic marker) expression, and predominant development of blast-forming unit erythroid colonies in semisolid medium. These data support the hypothesis that the divergence of primitive and definitive programs during human Pluripotent Stem Cells differentiation precedes the hemangioblast stage. Furthermore, we have shown that the inhibition of primitive hematopoiesis is associated with an increase in hematopoietic potential, which is a fruitful finding due to the growing need for lymphoid and myeloid Cells in translational applications.

  • cytokine free directed differentiation of human Pluripotent Stem Cells efficiently produces hemogenic endothelium with lymphoid potential
    Stem Cell Research & Therapy, 2017
    Co-Authors: Yekaterina Galat, Irina Elcheva, Svetlana Dambaeva, Philip M Iannaccone, Kenneth D Beaman, Aaruni Khanolkar, Vasiliy Galat
    Abstract:

    Background The robust generation of human hematopoietic progenitor Cells from induced or embryonic Pluripotent Stem Cells would be beneficial for multiple areas of research, including mechanistic studies of hematopoiesis, the development of cellular therapies for autoimmune diseases, induced transplant tolerance, anticancer immunotherapies, disease modeling, and drug/toxicity screening. Over the past years, significant progress has been made in identifying effective protocols for hematopoietic differentiation from Pluripotent Stem Cells and understanding stages of mesodermal, endothelial, and hematopoietic specification. Thus, it has been shown that variations in cytokine and inhibitory molecule treatments in the first few days of hematopoietic differentiation define primitive versus definitive potential of produced hematopoietic progenitor Cells. The majority of current feeder-free, defined syStems for hematopoietic induction from Pluripotent Stem Cells include prolonged incubations with various cytokines that make the differentiation process complex and time consuming. We established that the application of Wnt agonist CHIR99021 efficiently promotes differentiation of human Pluripotent Stem Cells in the absence of any hematopoietic cytokines to the stage of hemogenic endothelium capable of definitive hematopoiesis.

  • cytokine free directed differentiation of human Pluripotent Stem Cells efficiently produces hemogenic endothelium with lymphoid potential
    Stem Cell Research & Therapy, 2017
    Co-Authors: Yekaterina Galat, Irina Elcheva, Svetlana Dambaeva, Philip M Iannaccone, Kenneth D Beaman, Aaruni Khanolkar, Vasiliy Galat
    Abstract:

    The robust generation of human hematopoietic progenitor Cells from induced or embryonic Pluripotent Stem Cells would be beneficial for multiple areas of research, including mechanistic studies of hematopoiesis, the development of cellular therapies for autoimmune diseases, induced transplant tolerance, anticancer immunotherapies, disease modeling, and drug/toxicity screening. Over the past years, significant progress has been made in identifying effective protocols for hematopoietic differentiation from Pluripotent Stem Cells and understanding stages of mesodermal, endothelial, and hematopoietic specification. Thus, it has been shown that variations in cytokine and inhibitory molecule treatments in the first few days of hematopoietic differentiation define primitive versus definitive potential of produced hematopoietic progenitor Cells. The majority of current feeder-free, defined syStems for hematopoietic induction from Pluripotent Stem Cells include prolonged incubations with various cytokines that make the differentiation process complex and time consuming. We established that the application of Wnt agonist CHIR99021 efficiently promotes differentiation of human Pluripotent Stem Cells in the absence of any hematopoietic cytokines to the stage of hemogenic endothelium capable of definitive hematopoiesis. The hemogenic endothelium differentiation was accomplished in an adherent, serum-free culture syStem by applying CHIR99021. Hemogenic endothelium progenitor Cells were isolated on day 5 of differentiation and evaluated for their endothelial, myeloid, and lymphoid potential. Monolayer induction based on GSK3 inhibition, described here, yielded a large number of CD31+CD34+ hemogenic endothelium Cells. When isolated and propagated in adherent conditions, these progenitors gave rise to mature endothelium. When further cocultured with OP9 mouse stromal Cells, these progenitors gave rise to various Cells of myeloid lineages as well as natural killer lymphoid, T-lymphoid, and B-lymphoid Cells. The results of this study substantiate a method that significantly reduces the complexity of current protocols for hematopoietic induction, offers a defined syStem to study the factors that affect the early stages of hematopoiesis, and provides a new route of lymphoid and myeloid cell derivation from human Pluripotent Stem Cells, thus enhancing their use in translational medicine.

Nissim Benvenisty - One of the best experts on this subject based on the ideXlab platform.

  • Global Characterization of X Chromosome Inactivation in Human Pluripotent Stem Cells
    'Elsevier BV', 2019
    Co-Authors: Shiran Bar, Lev Roz Seaton, Uri Weissbein, Talia Eldar-geva, Nissim Benvenisty
    Abstract:

    Summary: Dosage compensation of sex-chromosome gene expression between male and female mammals is achieved via X chromosome inactivation (XCI) by employing epigenetic modifications to randomly silence one X chromosome during early embryogenesis. Human Pluripotent Stem Cells (hPSCs) were reported to present various states of XCI that differ according to the expression of the long non-coding RNA XIST and the degree of X chromosome silencing. To obtain a comprehensive perspective on XCI in female hPSCs, we performed a large-scale analysis characterizing different XCI parameters in more than 700 RNA high-throughput sequencing samples. Our findings suggest differences in XCI status between most published samples of embryonic Stem Cells (ESCs) and induced PSCs (iPSCs). While the majority of iPSC lines maintain an inactive X chromosome, ESC lines tend to silence the expression of XIST and upregulate distal chromosomal regions. Our study highlights significant epigenetic heterogeneity within hPSCs, which may bear implications for their use in research and regenerative therapy. : Bar et al. perform a large-scale analysis of X chromosome inactivation (XCI) in over 700 samples of human Pluripotent Stem Cells (PSCs). Erosion of XCI involves stable silencing of XIST and partial overexpression of distal X-linked genes and is prevalent in embryonic Stem Cells, but not in most induced PSCs. Keywords: X inactivation, human embryonic Stem Cells, human induced Pluripotent Stem Cells, XIS

  • immunologic and chemical targeting of the tight junction protein claudin 6 eliminates tumorigenic human Pluripotent Stem Cells
    Nature Communications, 2013
    Co-Authors: Uri Bendavid, Neta Nudel, Nissim Benvenisty
    Abstract:

    The tumorigenicity of human Pluripotent Stem Cells is a major safety concern for their application in regenerative medicine. Here we identify the tight-junction protein Claudin-6 as a cell-surface-specific marker of human Pluripotent Stem Cells that can be used to selectively remove Claudin-6-positive Cells from mixed cultures. We show that Claudin-6 is absent in adult tissues but highly expressed in undifferentiated Cells, where it is dispensable for human Pluripotent Stem cell survival and self-renewal. We use three different strategies to remove Claudin-6-positive Cells from mixed cell populations: an antibody against Claudin-6; a cytotoxin-conjugated antibody that selectively targets undifferentiated Cells; and Clostridium perfringens enterotoxin, a toxin that binds several Claudins, including Claudin-6, and efficiently kills undifferentiated Cells, thus eliminating the tumorigenic potential of human Pluripotent Stem cell-containing cultures. This work provides a proof of concept for the use of Claudin-6 to eliminate residual undifferentiated human Pluripotent Stem Cells from culture, highlighting a strategy that may increase the safety of human Pluripotent Stem cell-based cell therapies.

  • The tumorigenicity of human embryonic and induced Pluripotent Stem Cells.
    Nature reviews. Cancer, 2011
    Co-Authors: Uri Ben-david, Nissim Benvenisty
    Abstract:

    The unique abilities of human Pluripotent Stem Cells to self-renew and to differentiate into Cells of the three germ layers make them an invaluable tool for the future of regenerative medicine. However, the same properties also make them tumorigenic, and therefore hinder their clinical application. Hence, the tumorigenicity of human embryonic Stem Cells (HESCs) has been extensively studied. Until recently, it was assumed that human induced Pluripotent Stem Cells (HiPSCs) would behave like their embryonic counterparts in respect to their tumorigenicity. However, a rapidly accumulating body of evidence suggests that there are important genetic and epigenetic differences between these two cell types, which seem to influence their tumorigenicity.