Nerlov Group: Single cell biology projects.

 

Cellular mechanism of hematopoietic stem cell ageing

The function of the hematopoietic system is altered with age, resulting in decreased lymphocyte production and frequent anemia. To discriminate the roles of intrinsic and population-based changes to hematopoietic stem cells (HSCs) in this process we are using a combination of single cell transcriptome analysis and single cell functional studies. Global transcriptome analysis of single HSCs has identified both population-based and cell-intrinsic increases in platelet lineage priming. Functional studies, using single HSC transplantation, confirmed that this is reflected in HSC lineage output, identifying increase platelet bias as a key driver of HSC ageing. Future goals include interrogating the production of erythrocytes from aged HSCs, and in particular describing the abundance and red cell production, in both old mice and humans, of the diverse biased HSC subtypes found in the young hematopoietic system, as well as using single cell RNAseq to identify specific gene expression patterns of different biased HSCs, in order to determine how they are specified, and to allow their prospective identification in both the murine and the human hematopoietic systems.
Collaboration w/ Jacobsen lab.
 
Publication:
Amit Grover, Alejandra Sanjuan-Pla, Supat Thongjuea, Joana Carrelha, Alice Giustacchini, Adriana Gambardella, Iain Macaulay, Elena Mancini, Tiago Luis, Adam Mead, Sten Eirik W. Jacobsenand Claus Nerlov. Single cell global gene profiling reveals molecular and functional platelet bias of aged hematopoietic stem cells. Nat. Comm., in press.
 

Cellular pathways of hematopoietic lineage commitment

The myeloid cell types (neutrophils, monocytes/macrophages/eosinophils, basophils and mast cells) are generally assumed to originate from a common differentiation pathway, with the preGM/GMP as the first committed myeloid precursor. Using a combination of single cell gene profiling of preGMs, transcriptional reporters and single cell-based lineage readouts we have identified myeloid differentiation pathways that produce distinct subsets of myeloid cells, and which segregate from each other prior to their separation from lymphoid and megakaryocyte/erythroid lineage potentials, resulting in a revised roadmap of hematopoietic lineage commitment. Further studies aim to identify similar pathways in human hematopoiesis.
Collaboration w/ Jacobsen lab.
 
Publication:
Roy Drissen, Natalija Buza-Vidas, Supat Thongjuea, Alice Giustacchini, Adam Mead, Elena Mancini, Michael Lutteropp, Amit Grover, Sten Eirik W. Jacobsenand Claus Nerlov.Distinct myeloid progenitor differentiation pathways identified through single cell RNA sequencing. Nat. Immunol., in press.