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Human and Murine Hematopoietic Stem Cell Aging Is Associated with Functional Impairments and Intrinsic Megakaryocytic/Erythroid Bias.

Rundberg Nilsson A, Soneji S, Adolfsson S, Bryder D, Pronk CJ - PLoS ONE (2016)

Bottom Line: This was accompanied by functional impairments, including decreased lymphoid output and reduced proliferative potential.Downstream of human HSCs, we observed decreasing levels of common lymphoid progenitors (CLPs), and increasing frequencies of megakaryocyte/erythrocyte progenitors (MEPs) with age, which could be linked to changes in lineage-affiliated gene expression patterns in aged human HSCs.Therefore, our data support the notion that age-related changes also in human hematopoiesis involve the HSC pool, with a prominent skewing towards the megakaryocytic/erythroid lineages, and suggests conserved mechanisms underlying aging of the blood cell system.

View Article: PubMed Central - PubMed

Affiliation: Medical Faculty, Division of Molecular Hematology, Institution for Laboratory Medicine, Lund University, Lund, Sweden.

ABSTRACT
Aging within the human hematopoietic system associates with various deficiencies and disease states, including anemia, myeloid neoplasms and reduced adaptive immune responses. Similar phenotypes are observed in mice and have been linked to alterations arising at the hematopoietic stem cell (HSC) level. Such an association is, however, less established in human hematopoiesis and prompted us here to detail characteristics of the most primitive human hematopoietic compartments throughout ontogeny. In addition, we also attempted to interrogate similarities between aging human and murine hematopoiesis. Coupled to the transition from human cord blood (CB) to young and aged bone marrow (BM), we observed a gradual increase in frequency of candidate HSCs. This was accompanied by functional impairments, including decreased lymphoid output and reduced proliferative potential. Downstream of human HSCs, we observed decreasing levels of common lymphoid progenitors (CLPs), and increasing frequencies of megakaryocyte/erythrocyte progenitors (MEPs) with age, which could be linked to changes in lineage-affiliated gene expression patterns in aged human HSCs. These findings were paralleled in mice. Therefore, our data support the notion that age-related changes also in human hematopoiesis involve the HSC pool, with a prominent skewing towards the megakaryocytic/erythroid lineages, and suggests conserved mechanisms underlying aging of the blood cell system.

No MeSH data available.


Related in: MedlinePlus

Enrichment of age- and lineage-specific gene expression signatures for human HSPCs.(A-D): Age-associated enrichment of lineage-affiliated signatures. Conventional GSEA against lineage-associated gene sets of h-CLPs (A), h-MEPs (B) and h-GMPs (C) for differential enrichment between young (left) and aged (right) BM h-HSCs (permutation type: phenotypes, FDR < 0.25). Significantly enriched signatures are marked with blue borders if enriched to the left, and with red borders if enriched to the right. (D) High throughput GSEA of progenitor-associated signatures to young and aged h-HSCs using BubbleMap. Saturation of bubbles reflects significance (permutation type: phenotypes, B-Y FDR < 0.25). Color represents enrichment to the left side (blue, young) or to the right side (red, aged). The size of the bubbles reflects quantification of the nominal enrichment score (NES). The number of probes in respective gene sets are indicated within brackets. (E-K): Lineage-associated enrichment of age-affiliated signatures. (E-J) Conventional GSEA against age-associated h-HSC gene sets for differential enrichment to the depicted lineages (permutation type: gene sets, FDR < 0.05). Significantly enriched signatures are marked with blue borders if enriched to the left, and with red borders if enriched to the right. (K) High throughput GSEA of age-associated h-HSC signatures between h-CLPs, h-MEPs, and h-GMPs using BubbleMap. Saturation of bubbles reflects significance (permutation type: gene sets, B-Y FDR < 0.05). Color represents enrichment to the left (blue) or right (red) side.
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pone.0158369.g003: Enrichment of age- and lineage-specific gene expression signatures for human HSPCs.(A-D): Age-associated enrichment of lineage-affiliated signatures. Conventional GSEA against lineage-associated gene sets of h-CLPs (A), h-MEPs (B) and h-GMPs (C) for differential enrichment between young (left) and aged (right) BM h-HSCs (permutation type: phenotypes, FDR < 0.25). Significantly enriched signatures are marked with blue borders if enriched to the left, and with red borders if enriched to the right. (D) High throughput GSEA of progenitor-associated signatures to young and aged h-HSCs using BubbleMap. Saturation of bubbles reflects significance (permutation type: phenotypes, B-Y FDR < 0.25). Color represents enrichment to the left side (blue, young) or to the right side (red, aged). The size of the bubbles reflects quantification of the nominal enrichment score (NES). The number of probes in respective gene sets are indicated within brackets. (E-K): Lineage-associated enrichment of age-affiliated signatures. (E-J) Conventional GSEA against age-associated h-HSC gene sets for differential enrichment to the depicted lineages (permutation type: gene sets, FDR < 0.05). Significantly enriched signatures are marked with blue borders if enriched to the left, and with red borders if enriched to the right. (K) High throughput GSEA of age-associated h-HSC signatures between h-CLPs, h-MEPs, and h-GMPs using BubbleMap. Saturation of bubbles reflects significance (permutation type: gene sets, B-Y FDR < 0.05). Color represents enrichment to the left (blue) or right (red) side.

Mentions: In parallel with the transcriptional profiling of young and aged h-HSCs, we conducted expression analyses of h-MEPs, h-GMPs, and h-CLPs from 6 young BM donors. We chose this approach to objectively define the transcriptional profiles associated with lineage commitment. To evaluate enrichment of lineage-affiliated signatures (h-MEPs, h-GMPs, and h-CLPs; S3 Fig, S3 Table) to young or aged HSCs, we performed “conventional” gene set enrichment analysis (GSEA) [37] and also more high throughput GSEA BubbleMap analysis, which assesses enrichment between all possible pairwise comparisons [38] (Fig 3A–3D, S4 Table). Using conventional GSEA we found that both h-MEP-associated and h-GMP-associated signatures strongly associated with aged h-HSCs (Fig 3B and 3C). By contrast, the h-CLP-associated signature displayed a significant enrichment to young h-HSCs (Fig 3A). When applying BubbleMap analysis, only h-MEP-associated genes remained significantly enriched to aged h-HSCs (Fig 3D, S4 Table), indicating that the h-MEP-skewing in aged h-HSCs is the most prominent of the three comparisons made.


Human and Murine Hematopoietic Stem Cell Aging Is Associated with Functional Impairments and Intrinsic Megakaryocytic/Erythroid Bias.

Rundberg Nilsson A, Soneji S, Adolfsson S, Bryder D, Pronk CJ - PLoS ONE (2016)

Enrichment of age- and lineage-specific gene expression signatures for human HSPCs.(A-D): Age-associated enrichment of lineage-affiliated signatures. Conventional GSEA against lineage-associated gene sets of h-CLPs (A), h-MEPs (B) and h-GMPs (C) for differential enrichment between young (left) and aged (right) BM h-HSCs (permutation type: phenotypes, FDR < 0.25). Significantly enriched signatures are marked with blue borders if enriched to the left, and with red borders if enriched to the right. (D) High throughput GSEA of progenitor-associated signatures to young and aged h-HSCs using BubbleMap. Saturation of bubbles reflects significance (permutation type: phenotypes, B-Y FDR < 0.25). Color represents enrichment to the left side (blue, young) or to the right side (red, aged). The size of the bubbles reflects quantification of the nominal enrichment score (NES). The number of probes in respective gene sets are indicated within brackets. (E-K): Lineage-associated enrichment of age-affiliated signatures. (E-J) Conventional GSEA against age-associated h-HSC gene sets for differential enrichment to the depicted lineages (permutation type: gene sets, FDR < 0.05). Significantly enriched signatures are marked with blue borders if enriched to the left, and with red borders if enriched to the right. (K) High throughput GSEA of age-associated h-HSC signatures between h-CLPs, h-MEPs, and h-GMPs using BubbleMap. Saturation of bubbles reflects significance (permutation type: gene sets, B-Y FDR < 0.05). Color represents enrichment to the left (blue) or right (red) side.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4930192&req=5

pone.0158369.g003: Enrichment of age- and lineage-specific gene expression signatures for human HSPCs.(A-D): Age-associated enrichment of lineage-affiliated signatures. Conventional GSEA against lineage-associated gene sets of h-CLPs (A), h-MEPs (B) and h-GMPs (C) for differential enrichment between young (left) and aged (right) BM h-HSCs (permutation type: phenotypes, FDR < 0.25). Significantly enriched signatures are marked with blue borders if enriched to the left, and with red borders if enriched to the right. (D) High throughput GSEA of progenitor-associated signatures to young and aged h-HSCs using BubbleMap. Saturation of bubbles reflects significance (permutation type: phenotypes, B-Y FDR < 0.25). Color represents enrichment to the left side (blue, young) or to the right side (red, aged). The size of the bubbles reflects quantification of the nominal enrichment score (NES). The number of probes in respective gene sets are indicated within brackets. (E-K): Lineage-associated enrichment of age-affiliated signatures. (E-J) Conventional GSEA against age-associated h-HSC gene sets for differential enrichment to the depicted lineages (permutation type: gene sets, FDR < 0.05). Significantly enriched signatures are marked with blue borders if enriched to the left, and with red borders if enriched to the right. (K) High throughput GSEA of age-associated h-HSC signatures between h-CLPs, h-MEPs, and h-GMPs using BubbleMap. Saturation of bubbles reflects significance (permutation type: gene sets, B-Y FDR < 0.05). Color represents enrichment to the left (blue) or right (red) side.
Mentions: In parallel with the transcriptional profiling of young and aged h-HSCs, we conducted expression analyses of h-MEPs, h-GMPs, and h-CLPs from 6 young BM donors. We chose this approach to objectively define the transcriptional profiles associated with lineage commitment. To evaluate enrichment of lineage-affiliated signatures (h-MEPs, h-GMPs, and h-CLPs; S3 Fig, S3 Table) to young or aged HSCs, we performed “conventional” gene set enrichment analysis (GSEA) [37] and also more high throughput GSEA BubbleMap analysis, which assesses enrichment between all possible pairwise comparisons [38] (Fig 3A–3D, S4 Table). Using conventional GSEA we found that both h-MEP-associated and h-GMP-associated signatures strongly associated with aged h-HSCs (Fig 3B and 3C). By contrast, the h-CLP-associated signature displayed a significant enrichment to young h-HSCs (Fig 3A). When applying BubbleMap analysis, only h-MEP-associated genes remained significantly enriched to aged h-HSCs (Fig 3D, S4 Table), indicating that the h-MEP-skewing in aged h-HSCs is the most prominent of the three comparisons made.

Bottom Line: This was accompanied by functional impairments, including decreased lymphoid output and reduced proliferative potential.Downstream of human HSCs, we observed decreasing levels of common lymphoid progenitors (CLPs), and increasing frequencies of megakaryocyte/erythrocyte progenitors (MEPs) with age, which could be linked to changes in lineage-affiliated gene expression patterns in aged human HSCs.Therefore, our data support the notion that age-related changes also in human hematopoiesis involve the HSC pool, with a prominent skewing towards the megakaryocytic/erythroid lineages, and suggests conserved mechanisms underlying aging of the blood cell system.

View Article: PubMed Central - PubMed

Affiliation: Medical Faculty, Division of Molecular Hematology, Institution for Laboratory Medicine, Lund University, Lund, Sweden.

ABSTRACT
Aging within the human hematopoietic system associates with various deficiencies and disease states, including anemia, myeloid neoplasms and reduced adaptive immune responses. Similar phenotypes are observed in mice and have been linked to alterations arising at the hematopoietic stem cell (HSC) level. Such an association is, however, less established in human hematopoiesis and prompted us here to detail characteristics of the most primitive human hematopoietic compartments throughout ontogeny. In addition, we also attempted to interrogate similarities between aging human and murine hematopoiesis. Coupled to the transition from human cord blood (CB) to young and aged bone marrow (BM), we observed a gradual increase in frequency of candidate HSCs. This was accompanied by functional impairments, including decreased lymphoid output and reduced proliferative potential. Downstream of human HSCs, we observed decreasing levels of common lymphoid progenitors (CLPs), and increasing frequencies of megakaryocyte/erythrocyte progenitors (MEPs) with age, which could be linked to changes in lineage-affiliated gene expression patterns in aged human HSCs. These findings were paralleled in mice. Therefore, our data support the notion that age-related changes also in human hematopoiesis involve the HSC pool, with a prominent skewing towards the megakaryocytic/erythroid lineages, and suggests conserved mechanisms underlying aging of the blood cell system.

No MeSH data available.


Related in: MedlinePlus