Asymmetric cell division and cell fate

Asymmetric cell division & Cell fate: Understanding how unequal organelle partitioning during asymmetric cell division shapes cell identity

Mammals are composed of hundreds of specialized cell types, all of which originate from a small group of undifferentiated stem cells. In our lab, we investigate how asymmetric cell division contributes to the generation of this cellular diversity.

Asymmetric cell division drives the division of a single mother cell into two daughter cells that adopt distinct cell fates. This process relies on the unequal segregation of cellular components, which gives each daughter cell a unique identity. Notably, many of these fate-determining components are essential cell organelles – such as lysosomes, mitochondria, and autophagosomes – that are otherwise critical for maintaining cellular homeostasis.  

We aim to uncover the molecular mechanisms underlying the unequal segregation of organelles, and to understand how these mechanisms shape daughter cell identities in mammals.

To do this, we integrate the role of cortical polarity proteins, which influence both organelle partitioning and fate specification. These polarity proteins, localize asymmetrically along the cortex of dividing cells and orchestrate the mechanisms of asymmetric cell division. Polarity proteins can arise from within the stem cell (intrinsic) or be provided by neighboring cells in e.g. the stem cell niche (extrinsic), creating a complex regulatory landscape. Understanding how these signals interact, partition and modify cell organelle function during division  – individually and synergistically – is key to reveling how cell fate decisions are made. 

To dissect and untangle these processes with molecular resolution, we leverage the ‘synthetic polarization assay’ (Watson* & Krüger* et al., Cell 2023) - a synthetic biology approach that allows us to reconstitute asymmetric cell division in a whole population of mammalian culture cells, including stem cells. This assay offers precise control over both intrinsic and extrinsic polarity signals and enables high-throughput, molecular resolution analysis of asymmetric cell division – an essential event typically confined to specialized contexts within whole organisms.