Extracellular Regulation of the Mitotic Spindle and Fate Determinants Driving Asymmetric Cell Division

Abstract

Stem cells use mode of cell division, symmetric (SCD) versus asymmetric (ACD), to balance expansion with self-renewal and the generation of daughter cells with different cell fates. Studies in model organisms have identified intrinsic mechanisms that govern this process, which involves partitioning molecular components between daughter cells, frequently through the regulation of the mitotic spindle. Research performed in vertebrate tissues is revealing both conservation of these intrinsic mechanisms and crucial roles for extrinsic cues in regulating the frequency of these divisions. Morphogens and positional cues, including planar cell polarity proteins and guidance molecules, regulate key signaling pathways required to organize cell/ECM contacts and spindle pole dynamics. Noncanonical WNT7A/VANGL2 signaling governs asymmetric cell division and the acquisition of cell fates through spindle pole orientation in satellite stem cells of regenerating muscle fibers. During cortical neurogenesis, the same pathway regulates glial cell fate determination by regulating spindle size, independent of its orientation. Sonic hedgehog (SHH) stimulates the symmetric expansion of cortical stem and cerebellar progenitor cells and contributes to cell fate acquisition in collaboration with Notch and Wnt signaling pathways. SLIT2 also contributes to stem cell homeostasis by restricting ACD frequency through the regulation of spindle orientation. The capacity to influence stem cells makes these secreted factors excellent targets for therapeutic strategies designed to enhance cell populations in degenerative disease or restrict cell proliferation in different types of cancers.

Orienting Muscle Stem Cells for Regeneration in Homeostasis, Aging, and Disease

“…Meanwhile, aging muscle exhibits reduced symmetric divisions and reduced self-renewal (Bernet et al, 2014; Cosgrove et al, 2014; Price et al, 2014; Tierney et al, 2014). The insight that regulation of asymmetric satellite cell division is a significant nodal point that impacts the efficiency of regeneration has emerged as a concept relevant to many tissues (Smith et al, 2017). Intrinsic satellite cell heterogeneity, the ability to asymmetrically divide, and gene regulatory mechanisms underscore the clear hierarchal relationships within the satellite cell pool, and with progenitors.…”

Iterative and Complex Asymmetric Divisions Control Cell Volume Differences in Ciona Notochord Tapering

“…Asymmetric divisions are common in developing embryos, but the canonical models, such as C. elegans first cleavage and fly neuroblasts, all involve highly polarized cells that divide to give daughters of considerably different size and completely different fate [8,9,23,[26][27][28][29]. The asymmetric divisions in the Ciona notochord, however, are relatively subtle and do not involve any obvious segregation of cell identity.…”

The Stem Cell Division Theory of Cancer

“…Cell division can also lead to failures in the distribution of cell-fate determinants between the daughter cells. The differential partitioning of 11 cell fate determinants (e.g., transcription factors and mRNAs) between the daughter cells is known to induce changes in cell behavior and fate [82][83][84][85][86]. Errors in the distribution of cell fate determinants can disrupt the balance between symmetric and asymmetric cell division [82,83,87,88], which can lead to the accumulation of cell divisions in stem cells (Figure 2).…”