Direct Lineage Reprogramming: Strategies, Mechanisms, and Applications Jun Xu, Yuanyuan Du, Hongkui Deng  Cell Stem Cell  Volume 16, Issue 2, Pages 119-134 (February 2015) DOI: 10.1016/j.stem.2015.01.013 Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure 1 Historical View of the Development of Lineage Reprogramming Selected advances in the development of lineage reprogramming are highlighted in different colors. Green, blue, and red indicate the induction of terminally differentiated cell types, stem cells or progenitors/precursors, and in vivo lineage reprogramming, respectively. Texts above the timeline indicate studies in mice, and texts below the timeline indicate studies in humans. Cell Stem Cell 2015 16, 119-134DOI: (10.1016/j.stem.2015.01.013) Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure 2 Factors Involved in Lineage Reprogramming Reprogramming factors, including lineage-specific transcription factors, small molecules, epigenetic regulators, miRNAs, and pluripotency factors, are manipulated to direct cell fate toward the desired lineages. The ultimate downstream effects of these factors are the re-establishment of the GRN for the target cell type. Cell Stem Cell 2015 16, 119-134DOI: (10.1016/j.stem.2015.01.013) Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure 3 Emergence of a Novel Approach for the Generation of Functionally Mature Cells by Lineage Reprogramming The generation of functionally mature cells by lineage reprogramming benefits from the combination of cell fate determination and maturation factors. In addition to developmental clues, both cell fate determination and maturation factors can be identified through the comparison of global gene expression profiles in immature fetal cells and mature adult cells. Further analysis of the GRN in these groups could facilitate the discovery of key cell fate determination and maturation factors responsible for cell fate conversion and functional maturation, respectively. Finally, the combination of cell fate determination and maturation factors can convert the original cells into the desired cell type with fully functional maturation. Cell Stem Cell 2015 16, 119-134DOI: (10.1016/j.stem.2015.01.013) Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure 4 Novel Strategies for Large-Scale Induction of Lineage Conversion for Application Purposes To generate a large number of converted cells for application purposes, somatic cells can be induced into stem cells or progenitor/precursors and propagated prior to further differentiation into terminally differentiated cells. Another strategy is to induce a transient proliferating intermediate state during lineage conversion, and these intermediates can gradually stop proliferation and become functional terminal cells. Cell Stem Cell 2015 16, 119-134DOI: (10.1016/j.stem.2015.01.013) Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure 5 In Vivo Lineage Reprogramming for Cell Therapy Reprogramming factors can be delivered into the target in vivo site to induce the conversion of somatic cells into the desired cells, thereby repairing the impaired tissue in situ. The advantages and challenges of this strategy are highlighted. Cell Stem Cell 2015 16, 119-134DOI: (10.1016/j.stem.2015.01.013) Copyright © 2015 Elsevier Inc. Terms and Conditions