Molecular mechanisms of transcription factor mediated cell reprogramming: conversion of liver to pancreas

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.

Structural changes of pancreatic components under the conditions of long-time exposure to opioid in the experiment

“…Alanine aminotransferase is an endogenous enzyme from the group of transferases, a subgroup of aminotransferases, synthesized intracellularly, mainly by liver cells, but also found in pancreatic cells. The degree of increase in alanine aminotransferase activity indicates the severity of the cytolytic syndrome [28]. A significant increase in the activity of alanine aminotransferase in the blood serum of a white rat after 4 weeks of nalbuphine administration indicates the toxic effect of this drug, which apparently damages or destroys cells, including those of the pancreas.…”

CRGEM: Cellular Reprogramming using mechanism-driven Gene Expression Modulation

“…Cells of a particular type maintain their identity and behavioral properties with the help of dynamic activities of transcription factors (TFs) and their corresponding target genes [10]. In line with this, cellular reprogramming from one type to another is shown to be achieved by modulating the activities of specific transcription factors [11], [12]. However, the challenge lies in identifying the correct TFs for modulation given that there are estimated 19,000 protein-coding genes [13] and ∼1,600 TFs in humans [14].…”

Expression and clinicopathological characteristics of PDX1, PTF1A, and SALL4 in large and small ducts of ectopic pancreas located in gastro-duodenum and jejunum

“…Identification of pancreas/duodenum homeobox protein 1 (PDX1) as a key regulatory transcription factor during embryonic development (distinguishing one body part from another) is central to developing transdifferentiation protocols. Ectopic expression factors like PDX1, Neurogenin 3 (Ngn3), and MafBZIP Transcription Factor A (MafA) which are vector-delivered transcription factors, induce reprogramming through extensive transcriptional remodeling [ 7 ].…”