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Adult skull bone marrow is an expanding and resilient haematopoietic reservoir

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Koh et al. 2024 — Adult skull bone marrow is an expanding and resilient haematopoietic reservoir

Nature 636:172–181, 2024. DOI: 10.1038/s41586-024-08163-9 · PMID: 39537918 · PMC: PMC11618084 (open access). Senior author: Ralf H. Adams (Max Planck Institute for Molecular Biomedicine). Published online November 13, 2024.

TL;DR

Using imaging, mouse genetics, and pharmacological approaches across four age groups (young 10–14 weeks through geriatric >95 weeks), Koh et al. report that the bone-marrow of the adult skull undergoes lifelong vascular expansion rather than the vascular decline observed in the femur, resulting in an age-dependent increase in haematopoietic output. Skull bone marrow is also substantially protected against three canonical aging hallmarks — pro-inflammatory cytokine upregulation, adipogenesis, and loss of vascular integrity — that degrade the femoral niche. The authors conclude that the skull constitutes a “protected and dynamically expanding” haematopoietic reservoir whose contribution to systemic blood production grows with age. This central claim is currently contested (see § Contested / disputed below). gap/contradictory-evidence

Background

The bone-marrow niche supports hematopoietic-stem-cells (HSCs) throughout life; aging of this niche is a major driver of stem-cell-exhaustion and impaired immune regeneration (see hematopoietic-system). Established literature documents age-related deterioration in the femoral bone marrow: vascular rarefaction, adipocyte invasion, loss of endothelial cell integrity, and a pro-inflammatory shift that biases HSCs toward myeloid output. Whether all bone compartments share this trajectory, or whether anatomically distinct niches diverge, was unexplored prior to this study.

The skull (calvarial) bone marrow is anatomically distinct from long bones — it is flat, has distinct vascular architecture, and is in proximity to the meninges and brain vasculature. Emerging work on brain-skull cellular trafficking had made this compartment of increasing interest.

Study design and methods

Model: C57BL/6J mice, both sexes, across four age groups: young (10–14 weeks), middle-aged (31–37 weeks), old (52–75 weeks), geriatric (>95 weeks). Transgenic reporter lines included Flk1-GFP, Vav-mTmG, and Vav-KikGR.

Imaging approach: Confocal microscopy (Zeiss LSM980) of 80 μm thick cryosections, using immunofluorescence for CD31 and endomucin to mark blood vessel endothelia. Evans Blue for vascular leakage. Scanning electron microscopy for endothelial fenestration analysis. Dura mater whole-mount immunostaining (dura separated from calvarium prior to staining; used to distinguish vascular leakage in dura from calvarial BM). No tissue-clearing methods were used.

Human CT data: 128-channel multidetector CT in 36 human subjects (n=9 per age/sex group; ages 21–40 vs. 61–69 years) without contrast, measuring marrow area in skull cross-sections. Observational and non-mechanistic.

Hematopoietic output: Photoconversion of Vav-KikGR reporter cells to trace bone-marrow-resident HSPCs and their peripheral output; lethal-irradiation/shielding experiments to test compartment-specific reconstitution capacity.

Sample sizes: Most imaging experiments n=3–6 mice per group from 2–3 independent experiments; flow cytometry n=3–7 per group. Power calculations not reported in the abstract.

Key findings

Skull vasculature expands with age (opposite to femur)

In skull bone marrow, vascular area increased 6.4-fold in frontal bone and 3.6-fold in parietal bone between young and geriatric mice 1. Endomucin-positive endothelial signal increased 3.1-fold (frontal) and 7.0-fold (parietal). Sinus diameter increased 4.8-fold in parietal bone during aging. Caveolin-1+ interconnecting arterioles showed a 2.0-fold increase 1.

By contrast, femoral vascular density decreased 45.2% between middle-aged and old stages — the canonical long-bone aging trajectory 1.

Skull bone marrow volume and cellularity increase with age

Total haematopoietic cells in skull bone marrow increased 13.1-fold between young and geriatric mice 1. Skull thickness increased approximately 70% over this interval, accommodating expanded marrow volume. Long-term HSCs and Lin−Sca1+KIT+ (LSK) HSPCs increased in absolute number in aging skull marrow 1.

In humans, CT-based skull bone marrow area increased 83.2% in females and 24.6% in males comparing the 21–40 vs. 61–69 year age groups (n=9 per group) 1. gap/needs-replication

Skull haematopoietic output grows with age

Photoconversion tracing showed a marked age-dependent increase in systemic contribution from skull HSPCs. In lethal-irradiation/shielding experiments, head-shielded old mice were fully compatible with long-term survival after irradiation — demonstrating that skull marrow alone could support haematopoietic recovery. Hindlimb-shielded old mice did not survive beyond 200 days, despite having more total bone marrow 1. gap/needs-human-replication

Skull is protected from inflammaging

In skull marrow, only IFNγ showed significant upregulation in old versus young mice. In femur, 7 of 12 cytokines assayed showed increased expression in old mice, including TNF and IL-6 — the canonical inflammaging signature 1. The relative sparing of skull marrow from pro-inflammatory cytokine accumulation parallels findings on endothelial-cells integrity (see below).

Skull is protected from adipogenesis

Femoral bone marrow exhibited a 5.9-fold increase in adipocytes with aging (BODIPY quantification). Skull bone marrow showed minimal changes in lipid-filled mature adipocytes across the same age range 1.

Skull endothelial integrity is maintained

Scanning electron microscopy revealed regular fenestration patterns in skull endothelial cells in both young and old mice. Old femur endothelial cells showed irregular patterns with larger pores — indicative of compromised barrier function. Evans Blue vascular leakage assays were used to confirm vascular integrity differences 1.

Skull responds dynamically to physiological and pathological challenges

The skull vasculature and marrow underwent rapid, compartment-specific remodelling during pregnancy (physiological) and in response to stroke and experimental chronic myeloid leukaemia (pathological). These responses were highly distinct from femur, suggesting the skull niche integrates systemic signals differently 1.

Transplantation of Lin− cells from old skull induced a 2.2-fold expansion of skull vessels in recipient mice compared to young donor cells — indicating that aged skull HSPCs carry an intrinsic vascular-expansion signal 1.

Contested / disputed

The central claim of age-related vascular expansion in skull bone marrow is actively disputed. The following section documents a scientific rebuttal that is, as of the date of this page (2026-06-28), unpublished and not yet citable. The disagreement is recorded here for epistemic completeness; it should not be treated as settled evidence in either direction. gap/contradictory-evidence

Unpublished/forthcoming work presented publicly by the Kusumbe laboratory argues that the apparent vascular expansion reported by Koh et al. is an imaging artifact rather than a true biological phenomenon. The specific technical criticisms — not yet formalised in a peer-reviewed paper — centre on:

  1. Endomucin signal attribution without tissue-clearing. Koh et al. used 80 μm cryosections and confocal microscopy without whole-tissue clearing. The Kusumbe critique holds that endomucin signal in this configuration can be misattributed to nuclei or non-vascular structures due to confocal depth limits and incomplete section-level specificity, yielding apparent increases in “vascular” area that reflect staining artefact rather than new endothelium.

  2. Calvarial marrow shows standard aging signature in single-cell data. The same lab’s position is that when skull bone marrow is profiled with single-cell transcriptomics — which does not depend on immunofluorescence imaging — it shows the expected aging hallmarks: increased senescence markers, DNA damage response activation, declining endothelial cell numbers, and reduced angiogenic gene expression. This would place skull marrow on the same declining trajectory as femur, contradicting the Koh 2024 narrative.

What Koh et al. actually used: The imaging approach of Koh et al. relies on CD31/endomucin immunofluorescence in 80 μm cryosections; no tissue-clearing (CUBIC, iDISCO, CLARITY, etc.) is described in the methods. Whether three-dimensional cleared-tissue imaging would corroborate or contradict the vascular-expansion findings has not been published.

Current state: Neither a formal rebuttal nor a correspondence letter has been published as of 2026-06-28. Koh et al. (2024) is the only citable primary source on this topic. Downstream claims about skull marrow resilience should be held with low confidence until the methodological dispute is resolved in the peer-reviewed literature.

Extrapolation to humans

DimensionStatusNotes
Pathway conserved in humans?unknownHuman CT shows qualitatively similar skull marrow area expansion with age, but this is correlational; functional haematopoietic output and cytokine data are mouse-only
Phenotype conserved in humans?partialHuman CT-based bone marrow area increase is documented (n=36; n=9/group); no functional haematopoietic or vascular integrity data in humans
Replicated in humans?noAll mechanistic claims (vascular expansion, HSC numbers, cytokine profiles, adipogenesis, reconstitution capacity) are mouse-only; human evidence is limited CT anatomy

gap/needs-human-replication

Knowledge gaps

  1. Imaging-artefact question is unresolved. Tissue-clearing-based 3D vascular mapping of aged skull bone marrow in the same mouse age groups is needed to settle whether the apparent vascular expansion is a biological phenomenon or an immunofluorescence quantification artefact. gap/contradictory-evidence gap/needs-replication

  2. Single-cell transcriptomics of skull bone marrow endothelial cells in aging. High-resolution cell-type-resolved data would independently assess whether endothelial cell numbers and angiogenic gene expression actually increase with age in skull, as the imaging data imply. gap/needs-replication

  3. Human haematopoietic output from skull marrow is unmeasured. All functional reconstitution data (irradiation-shielding, photoconversion output) are mouse-based. Whether aged human skull marrow makes a meaningful compensatory contribution to haematopoiesis is unknown. gap/needs-human-replication

  4. Mechanism of skull’s apparent protection is undefined. What signals protect skull marrow from adipogenesis and inflammaging (if real) is not identified — the paper characterises the phenotype but does not mechanistically explain the compartment-specificity. gap/no-mechanism

  5. Longitudinal human data absent. The human CT finding is cross-sectional and observational (n=9 per age/sex group). Longitudinal within-individual measurements, with correction for BMI and haematological disease status, would be needed to establish a true age-related trajectory. gap/needs-replication

Significance for the wiki

  • bone-marrow — primary atomic home for the skull-marrow-resilience claim; should note this study and the methodological dispute.
  • hematopoietic-stem-cells — skull-compartment HSC expansion with age (if confirmed) would be a meaningful exception to the stem-cell-exhaustion narrative, potentially relevant to myeloid-bias models.
  • endothelial-cells — the vascular-expansion vs. vascular-decline compartment-specificity dispute is directly relevant to vascular niche biology.
  • stem-cell-exhaustion — the hallmark characterizes bone marrow niche decline as universal; Koh 2024 challenges universality for the skull compartment (contested).
  • chronic-inflammation — skull’s apparent resistance to cytokine upregulation with age is relevant to localized inflammaging models.
  • hematopoietic-system — navigational page; should cross-link this study as an outlier-observation entry.

See also

  • bone-marrow — canonical home of haematopoietic niche biology
  • bone — skeletal context; flat bone vs long bone architectural differences
  • hematopoietic-stem-cells — HSC self-renewal, myeloid bias, and niche dependency in aging
  • endothelial-cells — vascular niche component; CD31/endomucin markers used in this study
  • hematopoietic-system — system-level MOC for blood and immune tissue aging
  • stem-cell-exhaustion — hallmark challenged (contested) by this paper’s skull-compartment claim
  • chronic-inflammation — hallmark; skull cytokine data challenges universal inflammaging narrative

Footnotes

  1. koh-2024-skull-marrow-reservoir · n=3–7/group (imaging/FACS); 36 humans (CT) · in-vivo + observational · model: C57BL/6J mice (10 wk → >95 wk) + human CT · Koh BI et al. · Nature 636:172–181 · 2024 · doi:10.1038/s41586-024-08163-9 · PMID:39537918 · PMC:PMC11618084 · central imaging claims disputed by unpublished work (Kusumbe lab); see § Contested / disputed above ↩ ↩2 ↩3 ↩4 ↩5 ↩6 ↩7 ↩8 ↩9 ↩10 ↩11 ↩12

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