Satellite Cells in Muscular Dystrophy – Lost in Polarity Natasha C. Chang, Fabien P. Chevalier, Michael A. Rudnicki  Trends in Molecular Medicine  Volume 22, Issue 6, Pages 479-496 (June 2016) DOI: 10.1016/j.molmed.2016.04.002 Copyright © 2016 Elsevier Ltd Terms and Conditions

Figure 1 Modes of Satellite Stem Cell Division. Satellite stem cells can self-renew via symmetric or asymmetric cell divisions. A symmetric cell division along the planar axis (with respect to the myofiber) generates two stem cell daughters. Asymmetric cell divisions along the apicobasal axis give rise to a stem cell and a committed myogenic progenitor cell. Alternatively, satellite stem cells can directly express myogenic commitment factors (such as MYF5) to commit to the myogenic lineage and expand the progenitor population that will participate in muscle repair. Trends in Molecular Medicine 2016 22, 479-496DOI: (10.1016/j.molmed.2016.04.002) Copyright © 2016 Elsevier Ltd Terms and Conditions

Figure 2 Classical Model for the Establishment of Asymmetric Stem Cell Division during Neurogenesis in Drosophila. During interphase, the Par proteins are equally distributed in the cytoplasm. The binding of Lgl to aPKC inhibits (−−) its activity. Upon activation, Aurora kinase phosphorylates (P) Par-6 (1) leading to the activation (++) of aPKC (2) which phosphorylates Lgl (3) and forces its release (4). Baz binds to aPKC and completes the assembly of the Par complex (5). The Par complex can now phosphorylate Par-1 (6) and Numb (7), leading to their relocalization to the opposite pole of the cell (8). After activation by Polo kinase, Pon binds to phosphorylated Numb (9) and, together with Par-1, acts to inhibit Notch signaling (10), thus differentially controlling fate determination in the two daughter cells. Trends in Molecular Medicine 2016 22, 479-496DOI: (10.1016/j.molmed.2016.04.002) Copyright © 2016 Elsevier Ltd Terms and Conditions

Figure 3 Efficient Muscle Regeneration and Tissue Homeostasis Are Dependent on a Balance Between Symmetric and Asymmetric Satellite Stem Cell Divisions. Upon muscle injury within a healthy muscle, symmetric satellite cell expansion maintains the stem cell pool, while asymmetric cell divisions generate myogenic progenitors that will undergo expansion to regenerate the damaged tissue. In the context of aging, satellite stem cells favor commitment over self-renewal (increased asymmetric and reduced symmetric cell divisions) resulting in a gradual loss of stem cells. Over time, satellite stem cell decline and reduced entry into the cell cycle result in reductions of both stem and progenitor populations and an inability to efficiently perform muscle regeneration. In DMD, the loss of dystrophin-dependent polarity cues prevents satellite cells from undergoing asymmetric cell division. Shifting the balance towards symmetric stem cell division results in an increased number of satellite stem cells. An inability to perform asymmetric divisions and the associated mitotic defects may force the cells to enter a senescent state. Progressive depletion of committed progenitor cells over repetitive cycles of muscle degeneration–regeneration ultimately leads to muscle weakening. Trends in Molecular Medicine 2016 22, 479-496DOI: (10.1016/j.molmed.2016.04.002) Copyright © 2016 Elsevier Ltd Terms and Conditions

Figure 4 Key Figure: Consequences of Cell Polarity Defects and Therapeutic Strategies to Restore Satellite Cell Function in Dystrophic Satellite Cells (A) Normal satellite stem cells undergo asymmetric division upon dystrophin-dependent polarization of MARK2 and PARD3 to opposite sides along the apicobasal axis of the dividing cell. Cell fate determinants, such as mediators of Notch signaling, are asymmetrically distributed during mitosis to enforce different cell fates (stem cell self-renewal and myogenic commitment). (B) In dystrophin-deficient satellite cells, the expression of MARK2 is downregulated and PARD3 is equally distributed within the dividing cell. In the absence of polarity cues and abnormal mitotic progression, satellite stem cells undergo cell cycle arrest and may enter senescence. (C) Therapeutic approaches to restore cell polarity in DMD include AAV-mediated gene delivery of dystrophin or utrophin, in vivo genome editing with CRISPR/Cas, and direct pharmacological targeting of cell polarity effectors. (D) Therapeutic approaches to restore satellite cell function include treatment with WNT7a, inhibition of senescence-associated secreted factors, and stimulating the autophagy pathway to prevent senescence. Trends in Molecular Medicine 2016 22, 479-496DOI: (10.1016/j.molmed.2016.04.002) Copyright © 2016 Elsevier Ltd Terms and Conditions