Hematopoietic stem and progenitor cells as a reservoir for trained immunity
- Department of Pediatrics, Division of Infectious Diseases, and Stem Cells and Regenerative Medicine Center, Baylor College of Medicine and Texas Children’s Hospital, United States
- Program in Cancer and Cell Biology, Graduate School of Biomedical Sciences, Baylor College of Medicine, United States
- Department of Biomedical and Molecular Sciences, Queen’s University, Canada
- Program in Immunology and Microbiology, Graduate School of Biomedical Sciences, Baylor College of Medicine, United States
Figures
Figure 1
Hierarchical model of hematopoiesis.
Hematopoiesis is often depicted as a linear cell fate tree; however, recent investigation has shown developmental relationships between the various hematopoietic lineages. The LKS cell population comprises long-term hematopoietic stem cells (LT-HSCs), short-term HSCs (ST-HSCs), and multipotent progenitors (MPPs) in various stages. HSCs give rise to MPPs, with MPP1 representing early multipotent progenitors that are a metabolically active form of the most quiescent HSCs with the capacity for multi-lineage potential. Further downstream are specific multipotent progenitors (MPPs) which give rise to lineage-committed progenitors that are restricted in their differentiation potentials. MPP2 is biased to give rise to megakaryocyte–erythrocyte progenitors (MEPs), MPP3 to granulocyte–monocyte progenitors (GMPs), and MPP4 to common lymphoid progenitors (CLPs). While each of these multipotent progenitors is biased toward the production of specific lineage-committed progenitors, they can be skewed to favor the expansion of others, depending on the nature of the bone marrow microenvironment and timing of an insult. Lineage-committed progenitors develop into mature blood cells: MEP into platelets and erythrocytes, GMP into monocytes, basophils, neutrophils, and eosinophils, and CLP into pre-NK cells, pre-B cells, and thymocytes.
Figure 2
The engraftment potential of hematopoietic stem and progenitor cell (HSPC) subpopulations in transplant mouse models.
Murine transplant studies have been used to determine engraftment capacity of hematopoietic cells. Whole bone marrow (black line) can be transplanted into irradiated recipients to fully reestablish the hematopoietic system. Myeloid cells such as neutrophils and macrophages are the first to develop in the first few weeks post-transplantation, followed by lymphoid cells (Pietras et al., 2015; Ogonek et al., 2016). Hematopoietic stem cells (HSCs) are considered the main contributors to the long-term engraftment observed in hematopoietic transplant models. A single HSC (blue) can reconstitute the mouse hematopoietic system and can be serially transplanted for continued long-term hematopoiesis (Pietras et al., 2015; Oguro et al., 2013; Spangrude et al., 1988). Unlike HSCs and whole bone marrow, myeloid-biased downstream progenitors, such as multipotent progenitors (MPPs) (red), have been reported to sustain multilineage hematopoiesis for 4 weeks before their exhaustion and disappearance (Pietras et al., 2015; Oguro et al., 2013). The persistence of granulocyte–monocyte progenitors (GMPs) alone is even shorter compared to MPP3s (labeled in dashed green) (Pietras et al., 2015; Säwen et al., 2018). Of note, barcoding studies have shown much longer multilineage hematopoiesis from MPPs and GMPs in native, non-transplant conditions (Shaban et al., 2025).
Figure 3
Methods for analysis of DNA epigenetic modifications.
(A) ATAC-seq (Assay for Transposase-Accessible Chromatin with sequencing). This method determines chromatin accessibility by measuring open chromatin regions with Tn5 transposase, which inserts sequencing adapters into open chromatin regions. These regions are enriched in the sequencing results and correspond to larger sequencing peaks, reflecting where in the genome more transcriptional activity is occurring (Kaufmann et al., 2018; Cirovic et al., 2020; Mills et al., 2024; Cheong et al., 2023; Christ et al., 2018; Khan et al., 2020; de Laval et al., 2020; Kaufmann et al., 2022; Johansson et al., 2023; Sun et al., 2014; Zhang et al., 2017). (B) ChIP-seq (Chromatin Immunoprecipitation with sequencing). This method allows for the determination of protein-binding sites on DNA. Briefly, DNA sequences bound by transcription factors or histone modifications are captured via cross-linking, fragmentation, and immunoprecipitation using an antibody specific to the protein of interest. This method provides data in the form of genome-wide maps illustrating areas of histone modifications or transcription factor binding. (C) CUT&RUN-seq (Cleavage Under Targets and Release Using Nuclease sequencing). Much like ChIP-seq, CUT&RUN-seq provides genome-wide maps of protein–DNA interactions, but has a higher resolution and lower background. This method uses an antibody to bind a target protein, such as a transcription factor, followed by recruitment of micrococcal nuclease (A-MNase) fusion protein. This cleaves DNA only near the antibody-bound region, causing release of those fragments for sequencing (Ochando et al., 2023; Le et al., 2023). (D) CUT&TAG-seq (Cleavage Under Targets and TAGmentation sequencing). This method functions similarly to CUT&RUN-seq but provides data with even greater sensitivity and reduced background. After binding by an antibody to the protein of interest, a fusion of protein A to Tn5 transposase directly cuts and inserts sequencing adapters into the DNA at the DNA–protein-binding sites. (E) DNA methylation. Genomic DNA is digested with methylation-sensitive restriction enzymes (MSREs), cleaving unmethylated DNA while leaving methylated DNA intact. Digested DNA is then analyzed by reverse transcription-polymerase chain reaction (RT-PCR) with primers that flank the region of interest. Only methylated DNA is amplified, allowing for methylation to be determined by comparing the copies per reaction (Ct) between MSRE-treated and control samples (Verma et al., 2017; Mitroulis et al., 2018; Kain et al., 2023; Sun et al., 2024; Hormaechea-Agulla et al., 2021; Johansson et al., 2023).
Tables
Table 1
Hematopoietic stem and progenitor cell (HSPC) populations mediating trained immunity phenotypes.
| Cell type | TI experimental endpoint | Inducing stimulus | TI phenotype | Citations |
|---|---|---|---|---|
| Whole bone marrow | 20 weeks | BCG | Protection from M. tb infection | Kaufmann et al., 2018 |
| 1 year | M. tb | Susceptibility to M. tb | Khan et al., 2020 | |
| cKit enriched | 16 weeks to >1 year | M. avium | Cross protection | Kain et al., 2023 |
| H1N1 | ||||
| LSK | 13 weeks and secondary transplant | LPS | Protection from P. aeruginosa | de Laval et al., 2020 |
| LT-HSC | 13 weeks and secondary transplant | LPS | Protection from P. aeruginosa | de Laval et al., 2020 |
| 8 months | Fasciola hepatica excretory–secretory products (FHES) | Reduced susceptibility to induction of EAE | Cunningham et al., 2021 | |
| 1 year | M. tb | Inhibit trained immunity | Khan et al., 2020 | |
| ST-HSC/MPP3 | 4 weeks | BCG | ↑ ST-HSC, MPP3 | Kaufmann et al., 2018 |
| M. tb | ↓ ST-HSC, MPP3 | Khan et al., 2020 | ||
| Heme | ↑ ST-HSC, MPP3 | Jentho et al., 2021 | ||
| Western diet | ↓ MPPs | Christ et al., 2018 | ||
| GMPs | 1 week | β-Glucan | Anti-tumor immunity | Kalafati et al., 2020 |
| 1 year | COVID | Long-term inflammation | Cheong et al., 2023 | |
| 12 weeks | Sepsis | Post-sepsis immunosuppression | Bomans et al., 2018 |
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Hematopoietic stem and progenitor cells as a reservoir for trained immunity
eLife 14:e106610.
https://doi.org/10.7554/eLife.106610
