Computational Analysis of Altering Cell Fate
The notion of reprogramming cell fate is a direct challenge to the traditional view in developmental biology that a cell’s phenotypic identity is sealed after undergoing differentiation. Direct experimental evidence, beginning with the somatic cell nuclea
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Introduction The probe into the theoretical question of how to reprogram cell fate can be aided by identification and understanding of the gene regulatory network(s) (GRNs) that are implied in the transformation between one phenotype and another. A common conceptualization of this problem is the Waddington view of cellular differentiation [1] in which a ball rolls down a hilly landscape with several different valleys representing the multiple paths that undifferentiated cells may take in acquiring their differentiated identity (Fig. 1). In an energetic landscape sense, differentiation is represented as a spontaneous “downhill” process associated with typical development during an organism’s periods of growth and maturation. While it was a long-held consensus that this development was a permanent one-way process, experimental
Patrick Cahan (ed.), Computational Stem Cell Biology: Methods and Protocols, Methods in Molecular Biology, vol. 1975, https://doi.org/10.1007/978-1-4939-9224-9_17, © Springer Science+Business Media, LLC, part of Springer Nature 2019
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Hussein M. Abdallah and Domitilla Del Vecchio
Fig. 1 Waddington landscape of cell differentiation. In this metaphor for differentiation, cell fate specification is akin to a marble rolling down a hill with several different valleys that represent the diverse fates that cells with the same genetic encoding ultimately adopt. Along the way to differentiation, these cells are often lumped under the umbrella term of “stem cells,” though they have different potencies depending on their degree of differentiation. Zygotes and embryonic stem cells (ESCs) in the first few divisions after fertilization are totipotent and can give rise to an entire organism including the placenta and umbilical cord. When ESCs become pluripotent, they can continue to give rise to all three germ layers and thus an entire organism. Multipotent cells are adult stem cells that retain some potential for further differentiation, which is typically limited to a particular tissue type (e.g., hematopoietic cells, neural stem cells, mesenchymal stem cells) [2]. iPSC reprogramming as depicted is tantamount to an “uphill” movement from a somatic state (e.g., fibroblast) to the pluripotent state. Transdifferentiation as depicted is tantamount to directly transforming from one lineage to another (e.g., B-cell to macrophage, as shown in Xie et al. [3])
manipulations of cell fate during the second half of the twentieth century (such as somatic cell nuclear transfer [4–7] and transdifferentiation [8, 9]) began chipping away at this notion. In 2006, it was shattered entirely when Yamanaka and colleagues discovered that mouse fibroblasts could be reverted to what was coined an induced pluripotent stem cell (iPSC) state [10], a transition tantamount to an “uphill” climb in the Waddington landscape. Remarkably, this transformation was accomplished using the mere overexpression of a small cocktail of transcription factors (TFs): Oct4, Sox2, Klf4, and c-Myc (also known as “OSKM factors”). It is underst
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