Hematopoietic Stem Cells, Aging, and Chronic Inflammation

1 Takizawa et al. 2020 — HSC Protection from Stress-Induced Exhaustion

Full Citation:: Takizawa H, Boettcher S, Manz MG. Protection of hematopoietic stem cells from stress-induced exhaustion and aging. Experimental Hematology. 2020;85:1–5. DOI:: 10.1016/j.exphem.2020.04.002 PMID:: 32398455 Published:: May 2020 Study Design:: Expert perspective / mini-review Key Findings::

- HSCs can be induced to proliferate and differentiate in response to stress signals during infection, inflammation, chemotherapy, radiation, and aging
- With chronic or repeated stimulation, HSCs show progressive loss of function through telomere shortening, DNA damage accumulation, epigenetic drift, and clonal dominance
- NF-$\kappa$B is a central mediator: chronic cytokine exposure (TNF, IL-1, IL-6) forces HSCs out of protective quiescence into exhausting proliferation
- Exhausted HSCs produce an immune compartment skewed toward innate myeloid cells at the expense of adaptive lymphoid diversity
- Protective strategies include maintaining HSC quiescence, antioxidant protection, and reducing chronic inflammatory burden

Relevance to ME/CFS:: Provides mechanistic support for the HSC exhaustion speculation (Speculation Integrative Speculations). The repeated inflammatory stress of PEM episodes — each triggering acute immune activation and cytokine release — would by this mechanism plausibly deplete HSC reserves over time. The NF-\(\kappa\)B mechanism is particularly relevant given evidence for NF-\(\kappa\)B activation in ME/CFS immune cells. Certainty Assessment::

- *Quality:* Medium-High (Experimental Hematology; Manz is a leading HSC biologist)
- *Study type:* Expert perspective/mini-review
- *Limitations:* HSC exhaustion as a consequence of ME/CFS-type stress has not been directly measured; extrapolation from chemotherapy and ageing models to ME/CFS crashes is inferential; bone marrow studies in ME/CFS patients are lacking

2 Pietras et al. 2021 — Inflammation as a Regulator of HSC Function

Full Citation:: Pietras EM, Warr MR, Passegué E. Inflammation as a regulator of hematopoietic stem cell function in disease, aging, and clonal selection. Journal of Experimental Medicine. 2021;218(7):e20201541. DOI:: 10.1084/jem.20201541 PMID:: 34128949 PMCID:: PMC8220424 Published:: July 2021 Study Design:: Review article Key Findings::

- Chronic inflammation directly impairs HSC function, driving accelerated ageing, functional exhaustion, and clonal selection
- Transient LPS exposure primes aged HSCs to undergo accelerated differentiation at the expense of self-renewal, leading to irreversible HSC pool depletion
- NF-$\kappa$B activation is the central molecular regulator of HSC functional impairment by inflammatory signals
- Clonal haematopoiesis is a consequence of chronic inflammatory HSC pressure and itself amplifies systemic inflammation, establishing a feed-forward loop
- HSC exhaustion from chronic inflammation produces downstream immunosenescence: reduced immune diversity, impaired pathogen responses, and paradoxically increased autoimmunity

Relevance to ME/CFS:: Establishes the mechanistic pathway from chronic inflammation (documented in ME/CFS) to progressive HSC functional decline. The feed-forward loop — exhausted HSCs producing dysfunctional immune cells that generate more inflammation that further exhausts HSCs — maps precisely onto the vicious cycle proposed in the HSC exhaustion speculation. Certainty Assessment::

- *Quality:* High (*Journal of Experimental Medicine*; Passegué is a foremost HSC researcher)
- *Study type:* Comprehensive review with extensive experimental basis
- *Limitations:* Inflammation-to-HSC-exhaustion pathway is well-established in ageing and sepsis models but not yet studied specifically in ME/CFS; direct measurement of HSC function in ME/CFS patients is absent

Full Citation:: Morrison SJ, Scadden DT. The aging hematopoietic stem cell niche: a mini review. Frontiers in Hematology. 2025. DOI:: 10.3389/frhem.2025.1525132 Published:: 2025 Study Design:: Mini-review Key Findings::

- Ageing exerts profound impact on the haematopoietic system, leading to increased susceptibility to infections, autoimmune diseases, chronic inflammation, anemia, and haematologic malignancies
- Functional decline of HSCs is a primary driver of age-related haematologic conditions, operating through both HSC-intrinsic changes and bone marrow niche deterioration
- Adipogenic conversion of the marrow (red marrow replaced by yellow marrow) reduces HSC support and regenerative capacity
- Paediatric bone marrow is predominantly haematopoietically active; conversion to yellow marrow accelerates through adolescence and young adulthood

Relevance to ME/CFS:: Provides developmental context for the paediatric advantage in the HSC exhaustion speculation. The progressive conversion from red to yellow marrow through adolescence establishes a biological timeline for the declining HSC reserve that disadvantages adult patients. Also explains why adult ME/CFS patients cannot fully regenerate depleted HSC reserves: marrow niche has already undergone partial adipogenic conversion. Certainty Assessment::

- *Quality:* High (Frontiers in Hematology; Morrison and Scadden are leading HSC biologists)
- *Study type:* Mini-review; synthesises established ageing biology literature
- *Limitations:* Describes normal ageing biology; application to disease-accelerated HSC exhaustion is inferential; ME/CFS-specific marrow data are absent

3 Rossi et al. 2025 — Haematopoietic Ageing in Health and Lifespan

Full Citation:: Rossi DJ, Jamieson CHM, Weissman IL. Haematopoietic ageing in health and lifespan. Nature Cell Biology. 2025;27:195–207. DOI:: 10.1038/s41556-025-01739-1 Published:: January 2025 Study Design:: Review article Key Findings::

- Comprehensive review establishing HSC ageing as a systemic driver of organismal ageing, with particular emphasis on inflammaging and immunosenescence
- HSC ageing characterized by phenotypic and functional impairments from intrinsic HSC changes and niche deterioration
- Ageing HSCs show myeloid skewing — increased myeloid and reduced lymphoid output — producing innate immune hyperactivation at the expense of adaptive immune diversity
- HSC-derived chronic low-grade inflammation (inflammaging) contributes to age-related diseases beyond the haematopoietic system

Relevance to ME/CFS:: Establishes HSC ageing as a systemic driver of chronic inflammation and immune dysfunction. The myeloid skewing of ageing HSCs could explain simultaneous innate immune hyperactivation and adaptive immune deficiencies documented in ME/CFS. If ME/CFS accelerates HSC ageing, an inflammaging phenotype would emerge in younger patients than expected from normal biology. Certainty Assessment::

- *Quality:* High (*Nature Cell Biology*; Weissman is a pioneer of HSC biology)
- *Study type:* Comprehensive authoritative review
- *Limitations:* Describes normal ageing biology; whether ME/CFS represents accelerated HSC ageing requires direct bone marrow studies in ME/CFS patients, which are lacking