De novo hematopoietic (stem) cell generation — A differentiation or stochastic process?

The hematopoietic system is one of the earliest tissues to develop. De novo generation of hematopoietic progenitor and stem cells occurs through a transdifferentiation of (hemogenic) endothelial cells to hematopoietic identity, resulting in the formation of intra-aortic hematopoietic cluster (IAHC) cells. Heterogeneity of IAHC cell phenotypes and functions has stymied the field in its search for the transcriptional program of emerging hematopoietic stem cells (HSCs), given that an individual IAHC cannot be simultaneously examined for function and transcriptome. Several models could account for this heterogeneity, including a novel model suggesting that the transcriptomes of individual emerging IAHC cells are in an unstable/metastable state, with pivotal hematopoietic transcription factors expressed dynamically due to transcriptional pulsing and combinatorial activities. The question remains — how is functional hematopoietic cell fate established — is the process stochastic? This article touches upon these important issues, which may be relevant to the field's inability to make HSCs ex vivo.