Aging of Human Hematopoietic Stem and Progenitor Cells: History
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Comprehensive proteomics studies of human hematopoietic stem and progenitor cells (HSPC) have revealed that aging of the HSPC compartment is characterized by elevated glycolysis, in addition to an increased differentiation bias towards the myeloid lineage, alterations in DNA repair, and a decrease in lymphoid development. The increase in glycolytic enzyme activity is caused by the expansion of a more glycolytic HSPC subset. Based on glucose-uptake, human HSPC can be separated into GU-high, GU-inter and GU-low subsets. ScRNA-sequencing showed that the GU-high subset possesses all the molecular characteristics of senescent HSPC. This property may be exploited to enrich, visualise and trace senescence development in human bone marrow. Moreover, targeting central carbon metabolism may offer another alternative for developing "senolysis" strategies. 

  • hematopoietic stem and progenitor cells
  • aging
  • senescence signature
  • central carbon metabolism
  • glycolysis

1. Comprehensive and Unbiased Proteomics Studies

Comprehensive and unbiased proteomics studies of the HSPC have provided evidence that aging of the HSPC compartment is characterized by elevated glycolysis. Whereas significant changes found with this proteomics approach, such as an increase in differentiation bias towards the myeloid lineage, in DNA-repair, in cellular metabolism, and a decrease in proteins responsible for lymphoid development, as well as for stabilization of DNA replication have been described in murine transcriptomics studies, the enhanced central carbon metabolism activity in aged human HSPC is novel [1].

2. Evidence for Clonal Evolution of Senescent Population

Subsequent studies have demonstrated that the increase in glycolytic enzyme level is caused by the expansion of a HSPC subset that has become more glycolytic than the others and not on a per cell basis [2]. Provided with this knowledge, researchers developed a method to isolate the HSPC according to their glucose metabolic levels in three distinct categories: GUhigh, GUinter and GUlow subsets. The GUhigh subset is coupled with differentiation bias towards myeloid lineages [2].

3. Single-Cell Transcriptome Studies Revealed Senescent Population is Coupled with Elevated Glycolysis 

GSEA of the transcriptomes of the GUhigh versus GUlow subset, or GUhigh versus GUinter subsets have demonstrated that the gene sets for cell cycle arrest, MTORC1 signaling, inflammatory response, and anti-apoptosis pathways are significantly up-regulated in the GUhigh population [3]. Applying the transcriptomic “Aging Signature” gene set proposed by [4], the GUhigh subset achieves high scores for both of these “aging signatures”.

With this series of studies, researchers have produced a comprehensive proteomics and single cell transcriptomics atlas of molecular changes in human HSPC upon aging. Although many of the molecular deregulations are similar to those found in mice, there are significant differences. The most unique finding, however, is the association of elevated central carbon metabolism with senescence.

4. Significance for Identification, Enrichment, and Tracking of Senescence Development

Most of the current knowledge about the properties of senescent cells in the HSPC compartment is based on experiments in cultured cells and in murine models of aging [4]. There are no specific markers or marker constellation to identify and collect senescent cells for mechanistic studies. With the separation of HSPC according to glucose metabolic levels, researchers have provided evidence that researchers are able to enrich the senescent population in the GUhigh subset in the human hematopoietic system [5]. As the viability and functional integrity of this subset are well preserved, these cells can serve as starting material for further mechanistic characterization of human senescent HSPC.

5. Significance for Senolysis Treatment Strategies

In analogy to the Warburg effect in cancer cells, researchers' results have provided strong evidence for the dependency of senescent HSPC on elevated central carbon metabolism, as well as on MTORC1 pathways for survival [6][7]. During development and aging of HSPC, drastic metabolic shifts to meet the demand of hematopoiesis during transition occurs [8]. The glycolytic and MTORC1 pathways integrate inputs from nutrient and growth signals to regulate general cellular processes such as protein and lipid synthesis, autophagy, and metabolism [9]. In this respect, MTOR has been shown to regulate the senescence-associated secretory phenotype (SASP) and senescent growth arrest [9][10]. Based on upstream signaling of MTORC1, a relationship between carbohydrate consumption and MTORC1 activity has been demonstrated, specifically through the insulin growth factor pathway [9]. Multiple studies have demonstrated that caloric restriction can retard the aging decline [11]. Hence caloric restriction, or agents that modulate the glycolytic pathway such as Metformin may modulate glycolysis and MTORC1 pathways and eliminate the senescent population within the HSPC compartment.

Senescent cells and cancer cells share many common properties. Agents that block the apoptotic pathways that cancer cells are dependent on have been shown to be effective as senolytic drugs in aged mice [12]. ABT-263 and ABT-737 are examples that target the B cell lymphoma 2 (BCL-2) protein family members [13]. These drugs are however associated with toxic side effects such as neutropenia and thrombocytopenia. Targeting the central carbon metabolism or the closely related MTORC1 signaling pathway may offer better alternatives for developing senolysis strategies.

6. Unique Aspects

Researchers' series of studies are unique in the following aspects. First of all, almost all present-day knowledge on aging of HSPC and most proof-of-principle investigations for elimination of senescent cells have been gained from studies in mice. Without any doubt, great advances have been achieved, but the knowledge must be validated in the human system. Researchers' comprehensive transcriptome and proteome data sets have contributed to bridge this gap. As delineated in this entry, many of the principal mechanisms of senescence can be confirmed and yet there are differences. Another significant aspect is the discovery of the close association of elevated central carbon metabolism with senescence. Thus far, Isolation and collection of senescent cells have been extremely difficult as specific markers or marker constellation for their identification have yet to be developed. This is specially the case in human HSPC. The enrichment of HSPC, with all the characteristics of senescence by glucose metabolism, in conjunction with single cell high throughput technology, may represent an important stepping stone towards accurate visualization, collection and tracking of senescence in human bone marrow.

This entry is adapted from the peer-reviewed paper 10.3390/ijms23063028

References

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  2. Poisa‑Beiro, L.; Landry, T.J.; Sauer, S.; Yamamoto, A.; Eckstein, V.; Romanov, N.; Raffel, S.; Hoffmann, G.F.; Bork, P.; Benes, V.; Gavin, A.C.; Tanaka, M.; Ho, A.D. Glycogen accumulation, central carbon metabolism, and aging of hematopoietic stem and progenitor cells. Scientific Reports 2020, 10, 11597.
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  5. Poisa-Beiro L, Landry JJM, Raffel S, Tanaka M, Zaugg J, Gavin AC, Ho AD. Glucose Metabolism and Aging of Hematopoietic Stem and Progenitor Cells. Int J Mol Sci. 2022 Mar 11;23(6):3028. doi: 10.3390/ijms23063028.
  6. Warburg, O.H. Über den Stoffwechsel der Carcinomzelle. Wien. Klein. Wochenschr. 1925, 4, 534-536.
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  10. Herranz, N., Gallage, S.; Mellone, M.; et al. mTOR regulates MAP KAPK2 translation to control the senescence-associated secretory phenotype. Nat. Cell Biol. 2015, 17, 1205–1217.
  11. Mitchell, S.J.; Madrigal-Matute, J.; Scheibye-Knudsen, M.;et al. Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice. Cell Metab. 2016, 23, 1093–1112.
  12. Zhu, Y.; Tchkonia, T.; Fuhrmann-Stroissnigg, H.; …Kirkland, J.L. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 2016, 15, 428–435
  13. Chang J.; Wang, J.; Shao, L.; Laberge, R.M.; … Zhuo, D. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Medicine 2016, 22: 78-83.
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