Myeloid-biased hematopoietic stem cells have extensive self-renewal capacity but generate diminished lymphoid progeny with impaired IL-7 responsiveness

Abstract

IntroductionHematopoietic stem cells (HSCs) are capable of generating mature cells of all the hematopoietic lineages. Self-renewal capacity, the ability to proliferate without differentiation, is a similarly important hallmark of HSCs. The undifferentiated status of HSCs is characterized by promiscuous expression of genes, many of which were thought to be lineage specific. [1][2][3] Commitment to differentiation increasingly limits the developmental potential of the original HSCs by regulating the level of expression of lineage-specific genes. Lineage-specific genes then maintain the differentiated state and allow the committed progeny to react to environmental stimuli. Such extrinsic signals promote the survival and expansion of differentiated progeny. The commitment process is accompanied by loss of the ability to self-renew. 4,5 The mechanisms that control self-renewal and commitment are incompletely understood.It has been assumed that all HSCs have similar developmental potential. For example, the usual diagrams of HSC differentiation cascade that can be found in any textbook imply that the commitment process generates a myeloid and a lymphoid progenitor from each HSC. This is thought to assure that these lineages can be produced in equal measure. However, there is evidence that the HSC compartment contains distinct and separable subsets of HSCs that can differ in phenotype and primitiveness. "Primativeness" describes the proliferative capacity of an HSC, where primitive HSCs show delayed onsets of repopulation and then sustain production of mature progeny for a long time. Less primitive HSCs contribute rapidly, albeit transiently, to peripheral hematopoiesis. These types of HSCs can be separated to some extent. For example, HSCs that lack c-kit are more primitive, 6 whereas HSCs that express CD4 7 may be more mature than other types of HSCs. However, differences in primitiveness could be a reflection of the proliferative history of the HSC. 8 According to the generation-age hypothesis, 8 all HSCs may be born with the same level of primitiveness, but each proliferation results in loss of primitiveness. Thus, the subsets defined so far may reflect HSCs with different histories rather than cells with distinct functions. This raises the question of whether there is true heterogeneity in the HSC compartment.To define the composition of the HSC compartment, we developed an efficient approach to isolate clonally derived HSCs. Repopulating HSCs were isolated after limiting-dilution cultures on the stromal cell line S17. 9,10 The simplicity of the approach allowed the analysis of a large number of individual HSC clones. Among the HSC clones, we identified lineage-biased (Lin-bi) HSCs as a distinct class of HSCs. 10 Lin-bi HSCs give rise to cells of all hematopoietic lineages, but they generate noticeably skewed ratios of myeloid and lymphoid cells in the periphery. HSCs with similar properties had been identified previously, though they had not been characterized in detail. [10][11][12][13] The clonal analysis indic...

Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells

“…Overall, our data are consistent with behavioral features of individual HSC clones being established in development prior to young adulthood and persistently manifest under varying conditions. Lineage bias and proliferative potency has been demonstrated previously (Dykstra et al, 2007;Morita et al, 2010;Muller-Sieburg et al, 2004;Picelli et al, 2013), including at the clonal level (Sun et al, 2014b). The data here indicate that multiple other characteristics including sensitivity to inflammation or radiation are also clone-specific features.…”

The GOD of Hematopoietic Stem Cells: A Clonal Diversity Model of the Stem Cell Compartment

“…We found that My-bi HSC give rise to normal myeloid progeny but their lymphoid progeny showed a blunted response to Interleukin-7. 2 This lymphokine is central for the differentiation and homeostatic proliferation of lymphoid cells. 39,40 Analogously, Ly-bi HSC have an impaired ability to generate myeloid progeny.…”

“…Myeloid-biased (My-bi) HSC give rise to too few lymphocytes, and lymphoid-biased (Ly-bi) HSC generate too few myeloid cells. 2 All three types are normal HSC in that they have self-renewal capacity and can regenerate all hematopoietic lineages (pluripotency). Strikingly, the lineage bias is preserved through multiple rounds of serial transplantation: balanced HSC self-renew to give rise to daughter HSC that are also balanced, My-bi HSC give rise to My-bi daughter HSC, and Ly-bi produce Ly-bi daughter HSC.…”

“…2,4 All HSC can be classified by the ratio of lymphoid to myeloid cells that they generate upon differentiation. Three classes of HSC have been defined: balanced HSC that repopulate peripheral white blood cells in the same ratio of myeloid to lymphoid cells as seen in unmanipulated mice (about 15% myeloid and 85% lymphocytes).…”

“…HSC can differ in how rapidly they repopulate an ablated host after transplantation, how long they can produce mature cells, and how much they can selfrenew. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] The molecular and cellular mechanisms that generate such diversity in the HSC compartment have been much debated, but have been difficult to assess experimentally.…”