title: Concise Review: Reprogramming, Behind the Scenes: Noncanonical Neural Stem Cell Signaling Pathways Reveal New, Unseen Regulators of Tissue Plasticity With Therapeutic Implications.
abstract: Interest is great in the new molecular concepts that explain, at the level of signal transduction, the process of reprogramming. Usually, transcription factors with developmental importance are used, but these approaches give limited information on the signaling networks involved, which could reveal new therapeutic opportunities. Recent findings involving reprogramming by genetic means and soluble factors with well-studied downstream signaling mechanisms, including signal transducer and activator of transcription 3 (STAT3) and hairy and enhancer of split 3 (Hes3), shed new light into the molecular mechanisms that might be involved. We examine the appropriateness of common culture systems and their ability to reveal unusual (noncanonical) signal transduction pathways that actually operate in vivo. We then discuss such novel pathways and their importance in various plastic cell types, culminating in their emerging roles in reprogramming mechanisms. We also discuss a number of reprogramming paradigms (mouse induced pluripotent stem cells, direct conversion to neural stem cells, and in vivo conversion of acinar cells to β-like cells). Specifically for acinar-to-β-cell reprogramming paradigms, we discuss the common view of the underlying mechanism (involving the Janus kinase-STAT pathway that leads to STAT3-tyrosine phosphorylation) and present alternative interpretations that implicate STAT3-serine phosphorylation alone or serine and tyrosine phosphorylation occurring in sequential order. The implications for drug design and therapy are important given that different phosphorylation sites on STAT3 intercept different signaling pathways. We introduce a new molecular perspective in the field of reprogramming with broad implications in basic, biotechnological, and translational research.
  
  
  CONCLUSIONS
  Reprogramming is a powerful approach to change cell identity, with implications in both basic and applied biology. Most efforts involve the forced expression of key transcription factors, but recently, success has been reported with manipulating signal transduction pathways that might intercept them. It is important to start connecting the function of the classic reprogramming genes to signaling pathways that also mediate reprogramming, unifying the sciences of signal transduction, stem cell biology, and epigenetics. Neural stem cell studies have revealed the operation of noncanonical signaling pathways that are now appreciated to also operate during reprogramming, offering new mechanistic explanations.
authors.affiliation: Department of Internal Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Poser
authors.affiliation: Lieber Institute for Brain Development, Baltimore, Maryland, USA.
authors.forename: Josh G
authors.initials: JG
authors.lastname: Chenoweth
authors.affiliation: Lieber Institute for Brain Development, Baltimore, Maryland, USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Colantuoni
authors.affiliation: Department of Internal Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Masjkur
authors.affiliation: First Department of Pediatrics, University of Athens Medical School, Athens, Greece Aghia Sophia Children's Hospital, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Chrousos
authors.affiliation: Department of Internal Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.affiliation: Lieber Institute for Brain Development, Baltimore, Maryland, USA.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: McKay
authors.affiliation: Department of Internal Medicine III, Technische Universität Dresden, Dresden, Germany Center for Regenerative Therapies Dresden, Dresden, Germany andreas.theotokis@uniklinikumdresden.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Androutsellis-Theotokis
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C495457:HES3 protein, human; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014157:Transcription Factors
keywords: Cellular reprogramming; Cellular transdifferentiation; Hes3 protein; Induced pluripotent stem cells; Pancreatic islets; STAT3 transcription factor; Signal transduction