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Regenerative Medicine: Transdifferentiation in Vivo Cell Research (2014) 24:141-142

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Regenerative Medicine: Transdifferentiation in Vivo Cell Research (2014) 24:141-142 Cell Research (2014) 24:141-142. npg © 2014 IBCB, SIBS, CAS All rights reserved 1001-0602/14 $ 32.00 RESEARCH HIGHLIGHT www.nature.com/cr Regenerative medicine: Transdifferentiation in vivo Cell Research (2014) 24:141-142. doi:10.1038/cr.2013.165; published online 17 December 2013 A major challenge in regenera- the authors introduced different com- these in vivo transdifferentiation stud- tive medicine is the generation of binations of nine β-cell development- ies appeared to be different. In some functionally effective target cells to related transcription factors into the cases, it seemed to be a direct cellular replace or repair damaged tissues. pancreas of adult mice by adenovirus. conversion, such as from exocrine cells Transdifferentiation in vivo is a novel They found three factors (Pdx1, Ngn3, to β-cells, but in other cases, the initial strategy to achieve cell fate conver- and Mafa) that were required to convert cells might need to dedifferentiate into sion within the native physiological up to 20% of infected exocrine cells into an intermediate precursor stage before niche; this technology may provide insulin-producing β-cells. Lineage trac- final conversion to a new fate. For a time- and cost-effective alterna- ing experiments further demonstrated instance, Zhang and colleagues repro- tive for applications in regenerative the exocrine cell origins of the induced grammed astrocytes in the adult mouse medicine and may also minimize the β-cells. The absence of BrdU-labeled striatum to neuroblasts, which are neural concerns associated with in vitro cul- cells during the process excluded the precursor cells [9]. In their study, they ture and cell transplantation. possibility of a dedifferentiation stage. found that Sox2 alone was sufficient to Since its establishment, cell repro- The induced β-cells were characteristi- reprogram the endogenous quiescent gramming of somatic cells into induced cally similar to the endogenous islet β astrocytes to neuroblasts through a pluripotent stem cells (iPSCs) in vitro -cells in cell morphology, ultrastructure, proliferative stage. The induced neuro- has provided a fantastic tool for disease lineage marker expression and insulin blasts could subsequently differentiate modeling studies as well as presented secretion. However, the majority of the into neurons with exogenous expression potential applications in regenerative induced β-cells remained scattered or in of Brain-derived neurotrophic factor medicine [1]. However, in practice, small clusters without efficient integra- (BDNF) and Noggin, or with VPA (a the reprogramming of patient cells into tion into existing islets, which presum- histone deacetylase inhibitor) treatment. iPSCs and subsequent redifferentiation ably resulted in their limited capacity to Though the induced neuroblasts were into desired target cells is often an in- fully restore glucose homeostasis after proliferative, no tumor formation was efficient and time-consuming process. chemically induced pancreatic injury. detected during this study. More excit- As an alternative approach, transdif- Nonetheless, this report provided an ingly, neurons derived from induced ferentiation directly converts one cell encouraging proof-of-principle for in neuroblasts exhibited an elaborate neu- type into another, which bypasses many vivo transdifferentiation and stimulated ral morphology, possessed functional of the safety concerns associated with further studies. Using a similar method, voltage-gated sodium channels, and the pluripotent cell state. If this method Qian et al. [3] generated induced formed synapses with the endogenous can be applied in a safe and efficient cardiomyocyte-like cells from cardiac neurons, a sign of efficient integration manner in vivo, it can further help to fibroblastsin vivo by retroviral delivery into the local neural network. eliminate the undesired issues that may of three transcription factors (Gata4, These fascinating results from the arise during the in vitro culture and cell Mef2c, and Tbx5) into the myocardium recent progress in in vivo transdiffer- transplantation processes. based on a previous in vitro experiment entiation brought us new hopes and The idea of in vivo transdifferentia- [4]; Torper et al. [5] reported the suc- also raised new questions. For instance, tion is not a completely novel notion cessful conversion of resident astrocytes does transdifferentiation go through a in the stem cell field and it has been into mature neurons in situ by forced dedifferentiation stage or does it occur developing rapidly in recent years due to expression of Ascl1, Brn2a, and Myt11 directly? What is the master regulator in the rise in the discovery of transcription in the adult mouse striatum; and other the in vivo cell fate conversion process? factors that induce cell reprogramming. studies also reported the successful in Undisputedly, transcription factors A particularly remarkable advance in vivo transdifferentiation [6-8] (listed play key roles during this process in this field was the direct reprogramming in Table 1). which they build up a transition bridge of adult pancreatic exocrine cells into Although the methodologies were between initial and target cells. It has β-cells in 2008 [2]. Utilizing a cocktail, similar, the mechanisms involved in been reported that using the same initial npg 142 Table 1 Examples for in vivo transdifferentiation (TFs: transcription factors) Year Animal Initial cells Target cells TFs Delivery Ref. 2008 Mouse Pancreatic exocrine cells β-cells Pdx1, Ngn3, Mafa Adenovirus [2] 2012 Mouse Sox9+ cells in liver Insulin-secreting ducts Pdx1, Ngn3, Mafa Adenovirus [8] 2012 Mouse Non-myocytes (primarily Cardiomyocyte-like cells Gata4, Mef2c, Tbx5 Retrovirus [3] cardiac fibroblasts) 2012 Mouse Non-myocytes Cardiomyocyte-like cells Gata4, Hand2, Mef2c, Tbx5 Retrovirus [6] 2013 Mouse Astrocytes Neuron Ascl1, Brn2a, Myt1l Lentivirus [5] 2013 Mouse Astrocytes Neuroblast Sox2 Lentivirus [9] 2013 Mouse Embryonic and early post- Corticofugal projection Fezf2 Plasmid [7] natal callosal projection neurons in layer V/VI neurons in layer II/II cells, astrocytes could be converted through overexpression of OSKM in purposes. to neuroblasts and mature neurons by vivo [10]. Those iPSCs migrate to dif- Sox2 alone [9] and by combination of ferent tissues via the blood stream and Lina Fu1, *, Xiping Zhu1, *, Fei Yi2, *, Ascl1, Brn2a, Myt11 [5], respectively. differentiate on site or form teratomas. Guang-Hui Liu1, 3, With the appropriate combination of Certainly these tumor-forming cells Juan Carlos Izpisua Belmonte2, 4 transcription factors, even terminally would not be desired targets in any in differentiated cells can be directly con- vivo transdifferentiation study. There- 1National Laboratory of Biomacromolecules, verted into another terminally differen- fore, the scale and extent of the dedif- Institute of Biophysics, Chinese Academy of Sci- ences, Beijing 100101, China; 2Gene Expression tiated cell type. For example, Rouaux ferentiation process need to be carefully Laboratory, Salk Institute for Biological Studies, et al. [7] demonstrated that early monitored. 10010 North Torrey Pines Road, La Jolla, CA post-mitotic callosal neurons could be Considering the clinical advantages 92037, USA; 3Beijing Institute for Brain Disor- 4 converted into corticofugal neurons in of in vivo transdifferentiation, the asso- ders, Beijing 100069, China; Center for Regen- erative Medicine in Barcelona, Dr. Aiguader 88, vivo. Moreover, the type of initial cells ciated safety and efficacy issues are well Barcelona 08003, Spain selected also appears to have significant worth careful investigation. Can the *These three authors contributed equally to this impact on transdifferentiation ability induced target cells maintain their new work. a in vivo. The developmental origin of properties and functions in the long run? Correspondence: Guang-Hui Liu , Juan Carlos Izpisua Belmonteb the initial and target cells may directly Can the unnecessary damages to native aE-mail: [email protected] influence the efficiency and complexity tissue or non-targeted cells be mini- bE-mail: [email protected], [email protected] of the transdifferentiation process. This mized in induced transdifferentiation? is particularly evident in the transdiffer- Do infected but un-reprogrammed target References entiation of pancreatic exocrine cells to cells pose a safety concern? In order to β-cells, which occurred rapidly and ef- meet the criteria of potential clinical ap- 1 Takahashi K, Tanabe K, Ohnuki M, et al. Cell 2007; 131:861-872. ficiently [2]. This conversion benefited plication, it is also important to replace 2 Zhou Q, Brown J, Kanarek A, et al. Nature substantially from the few epigenetic viral vectors without jeopardizing the 2008; 455:627-632. differences between the two lineages as efficacy of transdifferentiation. Screen- 3 Qian L, Huang Y, Spencer CI, et al. Nature they share a common precursor. ing small compounds that mimic the 2012; 485:593-598. 4 Ieda M, Fu JD, Delgado-Olguin P, et al. Cell On the other hand, as the underly- role of transcription factor overexpres- 2010; 142:375-386. ing mechanisms of transdifferentiation sion is certainly a promising substitute 5 Torper O, Pfisterer U, Wolf DA, et al. Proc remain largely unknown, a step-wise for the use of virus. Furthermore, the Natl Acad Sci USA 2013; 110:7038-7043. methodology for transdifferentiating recent report from Abad et al. suggested 6 Song K, Nam YJ, Luo X, et al. Nature 2012; 485:599-604. cells cannot
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