Single Cell Transcriptomics to Understand HSC Heterogeneity and Its Evolution upon Aging

Abstract

Single-cell transcriptomic technologies enable the uncovering and characterization of cellular heterogeneity and pave the way for studies aiming at understanding the origin and consequences of it. The hematopoietic system is in essence a very well adapted model system to benefit from this technological advance because it is characterized by different cellular states. Each cellular state, and its interconnection, may be defined by a specific location in the global transcriptional landscape sustained by a complex regulatory network. This transcriptomic signature is not fixed and evolved over time to give rise to less efficient hematopoietic stem cells (HSC), leading to a well-documented hematopoietic aging. Here, we review the advance of single-cell transcriptomic approaches for the understanding of HSC heterogeneity to grasp HSC deregulations upon aging. We also discuss the new bioinformatics tools developed for the analysis of the resulting large and complex datasets. Finally, since hematopoiesis is driven by fine-tuned and complex networks that must be interconnected to each other, we highlight how mathematical modeling is beneficial for doing such interconnection between multilayered information and to predict how HSC behave while aging.

Hematopoietic Stem Cells and the Immune System in Development and Aging

“…Adult HSCs are characterized by heterogeneity, whereas fetal liver HSCs is homogeneously uniform in proliferation potential and differentiation [ 89 ]. Along with balanced multipotent cells, there is a pool of diverse HSCs that are biased to develop into a particular blood lineage [ 90 , 91 ]. Compared to embryonic HSCs, adults have a significantly reduced regenerative potential [ 92 ].…”

“…The described epigenetic modifications are accompanied by irregular changes in the expression of genes involved in DNA repair, metabolism, intracellular signal transduction, mitochondrial homeostasis, cell cycle regulation, and differentiation [ 91 ]. This impacts the phenotype and negatively affects the function HSCs with age.…”

“…Interestingly, about half of the differentially expressed genes revealed in different studies are cell membrane proteins/adhesion molecules ( Alcam, Cd34, Clca3a1, Dsg2, Itgb3 , and Selp ,) and cytokine receptors ( Csf2rb, Ebi3, Flt3, Ghr, Il1rapl2 , and Osmr ). Apparently, the role of these genes in the biology of HSCs was previously underestimated [ 91 , 140 ].…”