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Modeling physiological and pathological human neurogenesis in the dish.

Broccoli V, Giannelli SG, Mazzara PG - Front Neurosci (2014)

Bottom Line: However, significant hurdles remain that must be completely solved in order to facilitate the use of hPSCs in modeling (e.g., late-onset disorders) or in building therapeutic strategies for cell replacement.In this direction, new procedures have been established to promote the maturation and functionality of hPSC-derived neurons.Meanwhile, new methods to accelerate the aging of in vitro differentiating cells are still in development. hPSC-based technology has matured enough to offer a significant and reliable model system for early and late neurogenesis that could be extremely informative for the study of the physiological and pathological events that occur during this process.

View Article: PubMed Central - PubMed

Affiliation: Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute Milan, Italy.

ABSTRACT
New advances in directing the neuronal differentiation of human embryonic and induced pluripotent stem cells (hPSCs, abbreviation intended to convey both categories of pluripotent stem cells) have promoted the development of culture systems capable of modeling early neurogenesis and neural specification at some of their critical milestones. The hPSC-derived neural rosette can be considered the in vitro counterpart of the developing neural tube, since both structures share a virtually equivalent architecture and related functional properties. Epigenetic stimulation methods can modulate the identity of the rosette neural progenitors in order to generate authentic neuronal subtypes, as well as a full spectrum of neural crest derivatives. The intrinsic capacity of induced pluripotent cell-derived neural tissue to self-organize has become fully apparent with the emergence of innovative in vitro systems that are able to shape the neuronal differentiation of hPSCs into organized tissues that develop in three dimensions. However, significant hurdles remain that must be completely solved in order to facilitate the use of hPSCs in modeling (e.g., late-onset disorders) or in building therapeutic strategies for cell replacement. In this direction, new procedures have been established to promote the maturation and functionality of hPSC-derived neurons. Meanwhile, new methods to accelerate the aging of in vitro differentiating cells are still in development. hPSC-based technology has matured enough to offer a significant and reliable model system for early and late neurogenesis that could be extremely informative for the study of the physiological and pathological events that occur during this process. Thus, full exploitation of this cellular system can provide a better understanding of the physiological events that shape human brain structures, as well as a solid platform to investigate the pathological mechanisms at the root of human diseases.

No MeSH data available.


Related in: MedlinePlus

Induction and differentiation of iPSC-derived rosette neural progenitors. (A) Modulation of neurodevelopmental molecular pathways by different combinations of small molecules can direct hPSCs into rosette neural progenitors with different positional identities along the developing neural tube. (B) The hPSCs-derived rosette and the neural tube share the same spatial organization showing cells with a remarkable polarization and cell-junction compartmentalization. In addition, relative nuclei position is depending by the cell-cycle stage in both systems. (C) According to their specific early commit-ment, hPSCs-derived rosette neural progenitors generate distinct neuronal sub-types and, in the case of hNCPCs, even non-neuronal somatic cells.
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Figure 1: Induction and differentiation of iPSC-derived rosette neural progenitors. (A) Modulation of neurodevelopmental molecular pathways by different combinations of small molecules can direct hPSCs into rosette neural progenitors with different positional identities along the developing neural tube. (B) The hPSCs-derived rosette and the neural tube share the same spatial organization showing cells with a remarkable polarization and cell-junction compartmentalization. In addition, relative nuclei position is depending by the cell-cycle stage in both systems. (C) According to their specific early commit-ment, hPSCs-derived rosette neural progenitors generate distinct neuronal sub-types and, in the case of hNCPCs, even non-neuronal somatic cells.

Mentions: Further examination of these structures revealed that the rosettes are formed from neural progenitors. These neural progenitors are endowed with highly polarized morphology, as indicated by the presence of tight and adherence junctions at the side facing the internal lumen, while the external side is strongly enriched in laminin-rich extracellular matrix (Lazzari et al., 2006; Elkabetz et al., 2008; Colleoni et al., 2010). This architecture recapitulates the cellular organization of the neural tube, the embryonic primordium of the entire central nervous system (CNS), in both shape and function. In fact, within rosettes, the nuclei of neural progenitor cells undergo a stereotyped movement known as interkinetic nuclear migration, which is harmonized to the cell cycle stage and specific to authentic neural tube cells (Taverna and Huttner, 2010). Nuclei undergoing DNA synthesis localize at the outer edge of the neural tube, while mitotic divisions are confined to its innermost core, a pattern replicated in the same sequence by nuclei within the rosettes (Lazzari et al., 2006; Elkabetz et al., 2008; Colleoni et al., 2010). Therefore, rosettes share the same elementary organization of the developing neural tube; hence, they are equivalent to the developing neural tube with respect to structure and function (Figure 1). Rosette neural progenitors intertwine to create overlapping cellular layers; however, they remain constrained to the surface where they anchor. How rosettes can be adapted to the three-dimensional (3D) space, and which morphology and growth pattern they will follow in these culture conditions, have not yet been ascertained. This setting might enable the in vitro reproduction not only of neural tube organization, but also (and even more challenging) its organogenesis.


Modeling physiological and pathological human neurogenesis in the dish.

Broccoli V, Giannelli SG, Mazzara PG - Front Neurosci (2014)

Induction and differentiation of iPSC-derived rosette neural progenitors. (A) Modulation of neurodevelopmental molecular pathways by different combinations of small molecules can direct hPSCs into rosette neural progenitors with different positional identities along the developing neural tube. (B) The hPSCs-derived rosette and the neural tube share the same spatial organization showing cells with a remarkable polarization and cell-junction compartmentalization. In addition, relative nuclei position is depending by the cell-cycle stage in both systems. (C) According to their specific early commit-ment, hPSCs-derived rosette neural progenitors generate distinct neuronal sub-types and, in the case of hNCPCs, even non-neuronal somatic cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4109586&req=5

Figure 1: Induction and differentiation of iPSC-derived rosette neural progenitors. (A) Modulation of neurodevelopmental molecular pathways by different combinations of small molecules can direct hPSCs into rosette neural progenitors with different positional identities along the developing neural tube. (B) The hPSCs-derived rosette and the neural tube share the same spatial organization showing cells with a remarkable polarization and cell-junction compartmentalization. In addition, relative nuclei position is depending by the cell-cycle stage in both systems. (C) According to their specific early commit-ment, hPSCs-derived rosette neural progenitors generate distinct neuronal sub-types and, in the case of hNCPCs, even non-neuronal somatic cells.
Mentions: Further examination of these structures revealed that the rosettes are formed from neural progenitors. These neural progenitors are endowed with highly polarized morphology, as indicated by the presence of tight and adherence junctions at the side facing the internal lumen, while the external side is strongly enriched in laminin-rich extracellular matrix (Lazzari et al., 2006; Elkabetz et al., 2008; Colleoni et al., 2010). This architecture recapitulates the cellular organization of the neural tube, the embryonic primordium of the entire central nervous system (CNS), in both shape and function. In fact, within rosettes, the nuclei of neural progenitor cells undergo a stereotyped movement known as interkinetic nuclear migration, which is harmonized to the cell cycle stage and specific to authentic neural tube cells (Taverna and Huttner, 2010). Nuclei undergoing DNA synthesis localize at the outer edge of the neural tube, while mitotic divisions are confined to its innermost core, a pattern replicated in the same sequence by nuclei within the rosettes (Lazzari et al., 2006; Elkabetz et al., 2008; Colleoni et al., 2010). Therefore, rosettes share the same elementary organization of the developing neural tube; hence, they are equivalent to the developing neural tube with respect to structure and function (Figure 1). Rosette neural progenitors intertwine to create overlapping cellular layers; however, they remain constrained to the surface where they anchor. How rosettes can be adapted to the three-dimensional (3D) space, and which morphology and growth pattern they will follow in these culture conditions, have not yet been ascertained. This setting might enable the in vitro reproduction not only of neural tube organization, but also (and even more challenging) its organogenesis.

Bottom Line: However, significant hurdles remain that must be completely solved in order to facilitate the use of hPSCs in modeling (e.g., late-onset disorders) or in building therapeutic strategies for cell replacement.In this direction, new procedures have been established to promote the maturation and functionality of hPSC-derived neurons.Meanwhile, new methods to accelerate the aging of in vitro differentiating cells are still in development. hPSC-based technology has matured enough to offer a significant and reliable model system for early and late neurogenesis that could be extremely informative for the study of the physiological and pathological events that occur during this process.

View Article: PubMed Central - PubMed

Affiliation: Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute Milan, Italy.

ABSTRACT
New advances in directing the neuronal differentiation of human embryonic and induced pluripotent stem cells (hPSCs, abbreviation intended to convey both categories of pluripotent stem cells) have promoted the development of culture systems capable of modeling early neurogenesis and neural specification at some of their critical milestones. The hPSC-derived neural rosette can be considered the in vitro counterpart of the developing neural tube, since both structures share a virtually equivalent architecture and related functional properties. Epigenetic stimulation methods can modulate the identity of the rosette neural progenitors in order to generate authentic neuronal subtypes, as well as a full spectrum of neural crest derivatives. The intrinsic capacity of induced pluripotent cell-derived neural tissue to self-organize has become fully apparent with the emergence of innovative in vitro systems that are able to shape the neuronal differentiation of hPSCs into organized tissues that develop in three dimensions. However, significant hurdles remain that must be completely solved in order to facilitate the use of hPSCs in modeling (e.g., late-onset disorders) or in building therapeutic strategies for cell replacement. In this direction, new procedures have been established to promote the maturation and functionality of hPSC-derived neurons. Meanwhile, new methods to accelerate the aging of in vitro differentiating cells are still in development. hPSC-based technology has matured enough to offer a significant and reliable model system for early and late neurogenesis that could be extremely informative for the study of the physiological and pathological events that occur during this process. Thus, full exploitation of this cellular system can provide a better understanding of the physiological events that shape human brain structures, as well as a solid platform to investigate the pathological mechanisms at the root of human diseases.

No MeSH data available.


Related in: MedlinePlus