In vivo reprogramming of adult pancreatic exocrine cells to β-cells

By Qiao Zhou, Juliana R. Brown, A. Kanarek, J. Rajagopal, D. Melton. Nature, 2008

1,948 citations recorded by the source corpus.

One goal of regenerative medicine is to instructively convert adult cells into other cell types for tissue repair and regeneration. Although isolated examples of adult cell reprogramming are known, there is no general understanding of how to turn one cell type into another in a controlled manner. Here, using a strategy of re-expressing key developmental regulators in vivo, we identify a specific combination of three transcription factors (Ngn3 (also known as Neurog3) Pdx1 and Mafa) that reprograms differentiated pancreatic exocrine cells in adult mice into cells that closely resemble β-cells. The induced β-cells are indistinguishable from endogenous islet β-cells in size, shape and ultrastructure. They express genes essential for β-cell function and can ameliorate hyperglycaemia by remodelling local vasculature and secreting insulin. This study provides an example of cellular reprogramming using defined factors in an adult organ and suggests a general paradigm for directing cell reprogramming without reversion to a pluripotent stem cell state.

Subfields: Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/3d66ac679669d8fa2abed70b0d9171950fa0a865

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Citations in the corpus

Nuclear reprogramming to a pluripotent state by three approaches (2010, background): “and colleagues determined for generating iPS cells, two research groups (led by Melton and by Wernig) have deciphered the individual contributions of a panoply of transcription factors, identifying three that can convert one cell type to another (factors that can convert, for example, exocrine cells”
Control of Embryonic Stem Cell State (2011, background): “PcG proteins are thought to inhibit transcription, at least in part, by restraining poised RNA polymerase molecules (Stock et al., 2007; Zhou et al., 2008b).”
A Single-Cell Transcriptomic Map of the Human and Mouse Pancreas Reveals Inter- and Intra-cell Population Structure (2016, positive): “…ESR1, and RXRG. Combinations of cell type-specific transcription factors have allowed reprogramming between pancreatic lineages (Li et al., 2014; Zhou et al., 2008), and the role of these transcriptional regulators in development and the maintenance of cell type identity merit further…”
In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model (2013, methodology): “The mouse NeuroD1 gene was subcloned from the pAd NeuroD-I-nGFP (Zhou et al., 2008) (Addgene) and inserted into a pCAG-GFP-IRES-GFP retroviral vector (Zhao et al., 2006) (gift of Dr. Fred Gage) to generate pCAG-NeuroD1-IRES-GFP.”
Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors (2010, background): “…with Pdx1 and Mafa, can efficiently reprogram pancreatic exocrine cells into functional b cells in vivo, although the exocrine cells were known to have some potential to become islet cells in vitro and share a common parent cell with islet cells (Baeyens et al., 2005; Zhou et al., 2008).”
Pioneer transcription factors: establishing competence for gene expression. (2011, background): “These cases of trans-differentiation are paradigms for ‘‘direct reprogramming’’ approaches to create cells of biomedical interest, which include creating liver hepatocytes and pancreatic b cells (Shen et al. 2000; Sapir et al. 2005; Jarikji et al. 2007; Zhou et al. 2008; Yechoor et al. 2009).”
Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. (2011, neutral): “Such differentiation-state plasticity occurs in response to either genetic or microenvironmental perturbations (Deng et al., 2011; Thorel et al., 2010; Zhou et al., 2008) and has also been observed during normal developmental processes (Richard et al.”
Pancreas organogenesis: From bud to plexus to gland (2011, background): “During development, b-cells move from a MafBþ immature state to MafAþ/ MafBþ, and finally, to a MafAþ mature state.”