1. Modulating Cell Fate as a Therapeutic Strategy
Brian Lin, Priya Srikanth, Alison C. Castle, Sagar Nigwekar, Rajeev Malhotra, Jenna L. Galloway, David B. Sykes, Jayaraj Rajagopal 
Cell Stem Cell 
Volume 23, Issue 3, Pages (September 2018)
DOI: /j.stem
Copyright © 2018 Elsevier Inc. Terms and Conditions

2. Figure 1 Dedifferentiation in Epithelia
(A) In the epidermis, bulge, interfollicular epidermal, and upper pilosebaceous stem cells (PSU) normally produce differentiated cells restricted to their respective compartments. After injury, this restriction is lifted, allowing for bulge stem cells to contribute transiently to the epidermal compartment, epidermal stem cells to contribute to the generation of new hair follicles, and upper PSU stem cells to contribute to the interfollicular epidermis.
(B) In the airway, differentiated secretory cells can dedifferentiate after ablation of the basal stem cell population.
(C) In the stomach, chief cells, which produce pepsinogen and chymosin, can generate all of the cell types of the tissue. This ability is enhanced significantly after injury.
(D) In the intestine, differentiated cells are capable of broad levels of plasticity. After injury, reserve intestinal stem cells (rISCs), along with early transit amplifying (TA) cells and secretory progenitors, are capable of gaining stem cell function.
(E) In the cornea, ablation of the stem cells in the limbus induces dedifferentiation and migration of corneal cells to restore the limbus.
(F) In the olfactory epithelium, severe injury involving loss of the sustentacular (Sus) and olfactory sensory neurons (OSNs) induces dedifferentiation in neuronally specified progenitors (GBCinp) to become multipotent progenitors (GBCmpp).
Cell Stem Cell  , DOI: ( /j.stem )
Copyright © 2018 Elsevier Inc. Terms and Conditions

3. Figure 2 Pathologic Cell Fate Plasticity
(A) In Barrett’s esophagus, rare transitional basal cells in the squamocolumnar junction (SCJ) expand to generate intestinal metaplasia.
(B) In mucous metaplasia of the airway, chronic inflammation induces secretory cells to differentiate into goblet cells that produce excess mucus.
(C) In progressive osseous heteroplasia, activating mutations in the BMP pathway induce adipocyte progenitors to induce bone-forming transcriptional programs and deposit calcium.
(D) In calciphylaxis, vascular smooth muscle cells (VSMCs) in the tunica media induce ectopic Runx1 and begin to deposit calcium.
(E) In normal hematopoiesis, hematopoietic stem cells (HSCs) generate the common myeloid progenitor (CMP) that then give rise to myeloblasts, which can then generate monocytes or granulocytes. In acute myeloid leukemia, this differentiation step in myeloblasts is blocked and large amounts of myeloblasts are generated.
Cell Stem Cell  , DOI: ( /j.stem )
Copyright © 2018 Elsevier Inc. Terms and Conditions

4. Figure 3 Therapeutic Modulation of Cell Fate
(A) An example of differentiation therapy in which all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) are used in acute myeloid leukemia (AML) to force the differentiation of aberrant myeloblasts into monocytes and granulocytes.
(B) Localized administration of Notch inhibitors could prevent the differentiation of secretory cells into goblet cells, removing the source of excess mucus in airways diseases.
(C) Localized TNF-α or dorsomorphin could block Runx2 or BMP, respectively, and reverse calcification.
(D) Restoring the ability of Müller glia to express Ascl1, Sox2, and KLF4 could yield cells capable of dedifferentiation and restoration of lost rod and cone cells in the retina.
(E) Viral infection of the airway selectively targets short-lived luminal cells, preventing long-lasting treatment. Subsequent basal cell ablation or outright induction of dedifferentiation of virally transduced secretory cells could generate long-lasting basal stem cells carrying the proper gene therapy.
(F) Cardiac infarct generates fibroblast scarring in heart tissue alongside the death of cardiomyocytes. Directed reprogramming of scar fibroblasts into cardiomyocytes could be used to treat both the scar and restore the myocardium.
Cell Stem Cell  , DOI: ( /j.stem )
Copyright © 2018 Elsevier Inc. Terms and Conditions