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Single Cell RNA sequencing of hematopoiesis and erythropoiesis

Until recently, there were no strategies for describing the complete cellular and molecular trajectory of the early erythroid lineage, as it first arises from multipotential progenitors (MPPs), commits to a single lineage and progresses to the point where terminal differentiation is activated. To address this, we undertook single-cell RNA-sequencing (scRNA-seq) of mouse hematopoietic progenitors, in collaboration with Dr. Allon Klein (Harvard Medical School). By combining theoretical analysis of single-cell transcriptomic data with single-cell fate assays, we found that hematopoietic progenitors form a continuous, branching structure, with MPPs diverging either towards myeloid and lymphoid fates, or towards the erythroid, megakaryocyte and basophil/mast cell fates. This structure differs from classical models of hematopoietic development, which postulated differentiation to be a series of transitions between discrete developmental stages. Our model also highlights a novel coupling between the erythroid and basophil/mast cell fates.

This single-cell analysis identified candidate regulators of lineage commitment as well as novel growth factor regulators of erythropoiesis that we are currently investigating. It also allowed us to devise strategies for isolating pure populations of early erythroid progenitors (see 'Flow Cytometry' research page). Our lab is continuing to use scRNA-seq and other single-cell genomic approaches in the analysis of normal and abnormal hematopoiesis and erythropoiesis.

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References:

  • Tusi BK, Wolock SL, Weinreb C, Hwang Y, Hidalgo D, Zilionis R, Waisman A, Huh JR, Klein AM*, Socolovsky M*. Population snapshots predict early haematopoietic and erythroid hierarchies. Nature. 2018 Mar 1;555(7694):54-60. doi: 10.1038/nature25741. Epub 2018 Feb 21. PMID: 29466336; PMCID: PMC5899604. *joint corresponding authors
  • Weinreb C, Wolock S, Tusi BK, Socolovsky M, Klein AM. Fundamental limits on dynamic inference from single-cell snapshots. Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):E2467-E2476. doi: 10.1073/pnas.1714723115. Epub 2018 Feb 20. PMID: 29463712; PMCID: PMC5878004.
  • Khoramian Tusi B, Socolovsky M. High-throughput single-cell fate potential assay of murine hematopoietic progenitors in vitro. Exp Hematol. 2018 Apr;60:21-29.e3. doi: 10.1016/j.exphem.2018.01.005. Epub 2018 Jan 31. PMID: 29410050; PMCID: PMC5857247.