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Understanding the Cell-Intrinsic and Microenvironmental Influences on Cell Fate and Output of Hematopoietic Stem and Progenitor Cells at Single Clone Resolution
Professor Mark Dawson1
1Peter MacCallum Cancer Centre, Melbourne, VIC, AUSTRALIA
Background: The haematopoietic system is maintained by cellular hierarchies of rare stem and progenitor cells that give rise to numerous terminally differentiated cells with functional specialisation. Tissue-specific stem cells maintain a self-renewing state and are induced to differentiate by extrinsic stimuli within the niche. These signals modulate the cell-intrinsic transcriptional programs and consequently, cell fate decisions. This balance is dependent on the tissue microenvironment and is re-wired upon inflammation, tissue damage and cancer development. How the fate and output of individual stem/progenitor clones within a hierarchy are restricted by the tissue microenvironment is poorly understood.
Aims: The aim of this work is to uncouple the intrinsic and extrinsic determinants of clone fate within the hematopoietic hierarchy, allowing assessment of their contribution in vivo.
Methods: A powerful unbiased strategy to investigate the clonal dynamics of normal and malignant cells is the use of expressed cellular barcodes which couple lineage tracing with single-cell transcriptomic profiling. We have recently developed this approach- single cell profiling and lineage tracing (SPLINTR)- to identify that clonal dominance and output is a heritable non-genetic property in Acute Myeloid Leukaemia. To understand if cell fate in haematopoiesis is truly pre-destined by a particular transcriptional program or chromatin landscape we have adopted a similar strategy of barcoding and expanding hematopoietic stem and progenitor cells (HSPCs). Using this approach, we have investigated the heritability of HSPC clone fate. Moreover, we assess how the cell-intrinsic potential of HSPCs is restricted by the tissue and immune microenvironment to determine the output and fate of clones.
Results: Lineage tracing of transplanted HSPCs in mice indicate that engraftment and fate of clones is a highly cell-intrinsic, heritable property. Transplantation of sister clones into different tissue microenvironments reveals subsets of clones where cell-intrinsic mechanisms determine their fate or clones that have microenvironment-dependent cell fate. Using single cell profiling, we identify gene expression signatures that predict engraftment capacity and lineage bias of transplanted HSPCs. Collectively these data reveal the molecular determinants of engraftment and fate of transplanted HSPCs at the level of individual clones within a cellular hierarchy.
Conclusions: These data support a strong cell-intrinsic basis for engraftment, output and lineage bias in the hematopoietic hierarchy, which can be restricted by the microenvironment in particular sub-populations of stem and progenitor cells. We provide a new insight into the role of the host microenvironment in clonal expansion of transplanted HSPCs.
Speakers
Mark Dawson