Stem cell heterogeneity: implications for aging and regenerative medicine - PubMed (original) (raw)

Review

Stem cell heterogeneity: implications for aging and regenerative medicine

Christa E Muller-Sieburg et al. Blood. 2012.

Abstract

For decades, hematopoietic stem cells (HSCs) were thought to be a homogeneous population of cells with flexible behavior. Now a new picture has emerged: The HSC compartment consists of several subpopulations of HSCs each with distinct, preprogrammed differentiation and proliferation behaviors. These programs are epigenetically fixed and are stably bequeathed to all daughter HSCs on self-renewal. HSCs within each subset are remarkably similar in their self- renewal and differentiation behaviors, to the point where their life span can be predicted with mathematical certainty. Three subsets can be distinguished when HSCs are classified by their differentiation capacity: myeloid-biased, balanced, and lymphoid-biased HSCs. The relative number of the HSC subsets is developmentally regulated. Lymphoid-biased HSCs are found predominantly early in the life of an organism, whereas myeloid-biased HSCs accumulate in aged mice and humans. Thus, the discovery of distinct subpopulations of HSCs has led to a new understanding of HCS aging. This finding has implications for other aspects of HSC biology and applications in re-generative medicine. The possibility that other adult tissue stem cells show similar heterogeneity and mechanisms of aging is discussed.

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Figures

Figure 1

A new view of the hematopoietic differentiation tree. (A) The traditional model: A homogeneous population of HSCs drives the hematopoietic system. This implies that all HSCs in the population will react in the same way to identical extrinsic stimuli. On commitment, each HSC generates the same number of myeloid (red) and lymphoid (blue) progenitors. Homeostatic mechanisms (curved arrows) adjust myeloid and lymphoid cells to the typical ratios seen in blood. (B) The new model: Several populations of HSCs each with distinct, stable differentiation programs drive the hematopoietic system. The thickness of the arrows corresponds to the ability of the HSCs to generate progeny of the indicated type. Straight arrows indicate that the ratios of lymphoid to myeloid precursors are reflected in the periphery. My-bi HCSs produce few lymphocytes but standard levels of myeloid cells. The reverse is true for Ly-bi HSCs; they generate few myeloid cells but standard levels of lymphocytes. Bala HCSs generate more lymphocytes than myeloid cells (at least in mouse) and are called balanced because their output resembles the average output of mature cells from all HSC subsets together. All HSCs have self-renewal capacity (yellow arrow), and all HSCs give rise to all types of mature cells and thus are true multipotent stem cells.

Figure 2

Different HSCs may have different requirements for survival/self-renewal. Top: All HSCs in a culture experience the same stimuli. These may expand a subset of HSCs (blue), leave another subset untouched (green), but could be detrimental for other (purple, orange) HSCs. The outcome is a modest expansion of a subset of HSCs. Bottom: In vivo, HSCs reside in niches that might provide selective stimuli to different HSC subsets. This leads to optimal self-renewal conditions for each subset of HSCs. Ex vivo HSC expansion could depend on finding distinct conditions for different HSC subsets.

Figure 3

The heterogeneity of the HSC compartment derives from a limited number of distinct HSC classes. (A) HSC activity in several individual, clonally repopulated mice was followed for 7 months generating 3 segments for each repopulation kinetic. Shown are the percent donor type cells in blood measured at the indicated time points. (B) Distinct subsets of HSCs can be revealed when the repopulation kinetics are classified by symbolic analysis. Similarities between kinetics were quantified by Hamming distance. The squares represent the 54 possible HSC groups as defined by the 3 segments of the kinetics and a high (↑) versus low (↓) output of mature cells. Black squares represent the HSC groups actually found. The figures below the square are examples of the HSC subsets actually found. + indicates increase in mature cells over time; −, decrease; and ∼, no change. For details see Sieburg et al., This research was originally published in Blood.

Figure 4

The heterogeneity of life spans in the HSC compartment is derived from HSC clones with preprogrammed self-renewal capacity. (A) Single donor type HSCs were transplanted into individual hosts. Daughter HSCs were serially transplanted into multiple secondary, tertiary and, if possible, quaternary host to follow the HSC clones over extended periods. All HSCs have a limited life span, although the life span varies. (B) Representation of the serial transplants of an individual HSC demonstrating the synchronicity of HSCs within a clone. Note the similarities of the repopulation kinetics in the secondary hosts and the simultaneous extinction of all daughter HSCs in all tertiary hosts. Additional examples can be found in Sieburg et al. The behavior of daughter HSC contrasts with the extensive heterogeneity of secondary repopulation kinetics after a multiclonal graft (C). This representation exemplifies a multiclonal graft (2 × 105 BM cells) originally injected into a single ablated host. Blue line represents donor type cells in blood after the primary graft; and different colored lines, donor type cells in blood in secondary and tertiary hosts. This research was originally published in Blood.,

Figure 5

Developmental regulation of the HSC compartment. Each HSC has a limited life span, and the production of mature cells found in blood follows a ballistic curve from the start to the end of their life. Early in the life of the organism, Ly-bi (blue lines) are more frequent than My-bi (red) HSCs. On average, My-bi HSCs have a longer life span than other subsets of HSCs, leading to an accumulation of My-bi and a loss of Ly-bi HSCs as the organism ages. The bar above the graph shows how the HSC composition is reflected in the ratios of lymphoid to myeloid cells in blood. Because of the differences in self-renewal, My-bi HSCs will preferentially (but not exclusively) outlive the host as has been shown in serial transplants.

References

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Stem cell heterogeneity: implications for aging and regenerative medicine - PubMed (original) (raw)