Asymmetric cell division of mammary stem cells

Abstract

Somatic stem cells are distinguished by their capacity to regenerate themselves and also to produce daughter cells that will differentiate. Self-renewal is achieved through the process of asymmetric cell division which helps to sustain tissue morphogenesis as well as maintain homeostasis. Asymmetric cell division results in the development of two daughter cells with different fates after a single mitosis. Only one daughter cell maintains “stemness” while the other differentiates and achieves a non-stem cell fate. Stem cells also have the capacity to undergo symmetric division of cells that results in the development of two daughter cells which are identical. Symmetric division results in the expansion of the stem cell population. Imbalances and deregulations in these processes can result in diseases such as cancer. Adult mammary stem cells (MaSCs) are a group of cells that play a critical role in the expansion of the mammary gland during puberty and any subsequent pregnancies. Furthermore, given the relatively long lifespans and their capability to undergo self-renewal, adult stem cells have been suggested as ideal candidates for transformation events that lead to the development of cancer. With the possibility that MaSCs can act as the source cells for distinct breast cancer types; understanding their regulation is an important field of research. In this review, we discuss asymmetric cell division in breast/mammary stem cells and implications on further research. We focus on the background history of asymmetric cell division, asymmetric cell division monitoring techniques, identified molecular mechanisms of asymmetric stem cell division, and the role asymmetric cell division may play in breast cancer.

Patterning and growth are coordinated early in the cell cycle

“…Regulation of CYCLIN D/CDKs is a target of many cancer therapies [66][67][68][69][70]. Furthermore, defects in division plane orientation and asymmetric division have recently been implicated in the genesis of breast and other cancers [7,71]. Most studies of cell cycle control have been in single-cell organisms or cell lines.…”

“…Due to intrinsic and extrinsic cell polarity, a 90-degree rotation of the division plane determines whether a cell will divide asymmetrically (producing daughter cells with different fates) or symmetrically (producing daughter cells with similar fates) [5,6]. The wrong choice can lead to over proliferation of cells, resulting in aberrant morphogenesis or tumorigenesis [7][8][9]. Developmental regulators that specify cell fate and directly interface with the cell cycle machinery [10][11][12] are likely arbiters of this decision, but challenges in long-term, multicolor imaging in multicellular organisms have limited knowledge about how these regulators dynamically control cell division in situ.…”

Regulation of epidermal stratification and development by basal keratinocytes

“…and K10, respectively, contributing to the cytoskeleton formation (Jeong et al, 2020). In early embryonic development, symmetric cell division of basal keratinocytes promotes proliferation along the direction parallel to the basal layer, therefore, coordinating fetal growth and epidermal tissue elongation (Chhabra & Booth, 2021).…”

“…Basal keratinocytes at the proliferation stage and those exiting the cell cycle express keratin K5 and K14 heterodimer proteins, and K1 and K10, respectively, contributing to the cytoskeleton formation (Jeong et al, 2020). In early embryonic development, symmetric cell division of basal keratinocytes promotes proliferation along the direction parallel to the basal layer, therefore, coordinating fetal growth and epidermal tissue elongation (Chhabra & Booth, 2021). Subsequently, asymmetric cell division of basal keratinocytes facilitates skin delamination, with one of the daughter cells detaching and migrating upward from the basement membrane (Lechler & Fuchs, 2005).…”

“…During the early stage of mouse embryogenesis, basal keratinocytes are a monolayer of epithelium constructed via symmetric cell division. When stratification initiates at E14.5, the mitotic spindle starts to tilt and reorients toward the basal tissue plane, and thus, the proliferating basal cells divide symmetrically along the basal plane (Chhabra & Booth, 2021; Lechler & Fuchs, 2005). As stratification continues, at E15.5, about 70% of cells begin to divide asymmetrically along the plane perpendicular to the basal layer, during which spindle orientation depends on PKC, proteinase‐activated receptor 3 ( par3 ), proteinase‐activated receptor 6 ( par6 ), leucine‐glycine‐asparagine (LGN), and nuclear mitotic apparatus (NuMA) (Hu et al, 2022; Polverino et al, 2021).…”