Abstract
Transdifferentiation is a type of cellular reprogramming involving the conversion of one differentiated cell type to another. This remarkable phenomenon holds enormous promise for the field of regenerative medicine. Over the last 20 years techniques used to reprogram cells to alternative identities have advanced dramatically. Cellular identity is determined by the transcriptional profile which comprises the subset of mRNAs, and therefore proteins, being expressed by a cell at a given point in time. A better understanding of the levers governing transcription factor activity benefits our ability to generate therapeutic cell types at will. One well-established example of transdifferentiation is the conversion of hepatocytes to pancreatic β-cells. This cell type conversion potentially represents a novel therapy in T1D treatment. The identification of key master regulator transcription factors (which distinguish one body part from another) during embryonic development has been central in developing transdifferentiation protocols. Pdx1 is one such example of a master regulator. Ectopic expression of vector-delivered transcription factors (particularly the triumvirate of Pdx1, Ngn3 and MafA) induces reprogramming through broad transcriptional remodelling. Increasingly, complimentary cell culture techniques, which recapitulate the developmental microenvironment, are employed to coax cells to adopt new identities by indirectly regulating transcription factor activity via intracellular signalling pathways. Both transcription factor-based reprogramming and directed differentiation approaches ultimately exploit transcription factors to influence cellular identity. Here, we explore the evolution of reprogramming and directed differentiation approaches within the context of hepatocyte to β-cell transdifferentiation focussing on how the introduction of new techniques has improved our ability to generate β-cells.
Highlights
The history of cell reprogramming, or the manipulation of cellular identity, spans a century of technological and conceptual innovation across developmental biology, biochemistry and medicine
We examine how transdifferentiation protocols are evolving to ever more faithfully recapitulate normal developmental biology using increasingly sophisticated biomimetic techniques and ectopic transcription factor expression
Cell reprogramming can be defined as the process of effecting stable change to cellular identity through revision of the transcriptional profile via manipulation of epigenetic modifiers
Summary
The history of cell reprogramming, or the manipulation of cellular identity, spans a century of technological and conceptual innovation across developmental biology, biochemistry and medicine (for reviews see [1,2]). Part 1 of 2 (A) Schematic representation of embryological differentiation from zygote to differentiated somatic cell (β-cell, hepatocyte), the directed differentiation of OKSM iPSCs to β-cell and the transdifferentiation of hepatocytes to β-cell using pancreatic master regulator transcription factors (Tgif2, Pdx1, Ngn3, NeuroD1, MafA). Ectopic expression of pancreatic transcription factors (Pdx1, MafA, Ngn3, Tgif2, NeuroD1) can induce or contribute to transdifferentiation to a β-cell phenotype.
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