Hematopoietic Stem Cell Heterogeneity

Hematopoietic stem cells (HSCs) are defined by their ability to sustain the life-long production of mature blood cells of all lineages and to repopulate all hematopoietic lineages after radiation of chemically induced cytotoxic insult. Healthy HSCs are capable of the following:

• Long-term multilineage reconstitution and in situ recovery of the hematopoietic system.
• Long-term engraftment and multilineage repopulation after adoptive transplant into preconditioned recipients.

Previous research, such as isolation and identifying human HSCs, showed that the population of HSCs is heterogeneous. However, numerous studies have defined phenotypic and functional heterogeneity within the HSC pool. Furthermore, they have revealed the coexistence of several HSC subsets with distinct proliferation, self-renewal, and differentiation potentials. These findings have transformed our perception of HSCs as a functionally uniform pool to that of a heterogeneous pool consisting of different HSC subsets.

Causes of HSC Heterogeneity

Recent scientists brought up important questions about the origins of HSC heterogeneity. However, the origins of HSC heterogeneity and intrinsic and extrinsic factors that may shape the functional diversification of HSCs are not well understood. These factors may include the following:

• Differential genetic and epigenetic reprogramming during early development and cell maturation.
• Differential localization in bone marrow niches.
• Genetic and epigenetic reprogramming is brought on by responses to different molecular and cellular stimuli.

Heterogeneity in HSC Self-Renewal Capacity

Scientists found that the transplanted HSCs could produce mature blood cells in the body, but with considerable differences in time spans. Subsequently, fluorescence-activated cell sorting (FACS) was used to classify HSCs into multipotent cells with long-term, mid-term and short-term self-renewal capacity based on different cellular markers. Simultaneous single-cell transplantation experiments showed that the self-renewal potential of mouse HSCs differed significantly between primary and secondary transplantation. This has even been observed using the most stringently defined phenotypic HSC subset. These findings have challenged the idea of functionally homogeneous HSC subsets and suggest that individual HSCs possess an almost unique capability to self-renew and repopulate irradiated hosts.