Clonal determinants of stem cell heterogeneity

Clonal determinants of stem cell heterogeneity

Alejo Rodríguez-Fraticelli

IRB, Barcelona

Date: 30/06/2022
Time: 12:30
Host: Xosé R. Bustelo
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For decades, biologists have noted that stem-cells in adult tissues show extensive functional heterogeneity. Observations of clonal heritability in hematopoietic stem cell (HSCs) lineage biases have suggested that this heterogeneity is determined by intrinsic and heritable molecules. However, a detailed understanding of the mechanisms driving the variation in tissue stem cell behaviors has remained elusive. We have previously shown that expressed barcodes can enable simultaneous read-out of transcriptome and clonal information from the same single cell. Using expressed barcodes, we are carrying out extensive dynamic analysis of states and fates for thousands of differentiating clones in parallel to reveal novel regulators of fate decisions. Long-term clonal analysis across serial transplantation experiments revealed intrinsic and heritable states driving differences in self-renewal properties. We have recently extended these studies to understand the process of aging and malignancy, identifying specific subsets of clones that expand and self-renew massively with reduced differentiation capacity. In sum, we show that connecting cellular states and cellular fates through high-resolution lineage tracing can be used to identify determinants for a variety of relevant stem cell properties. These approaches could be highly impactful for our understanding of disease heterogeneity, including cancer, and for the optimization of cell therapies.