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Coupling Inflammatory Resolution to Osteogenesis: Lymphatic Vessels as Stage-specific Niche Regulators in Skeletal Healing

ABSTRACT:

Skeletal healing requires the coordinated resolution of inflammation and precise lineage commitment of mesenchymal progenitors, yet the mechanisms coupling these processes remain incompletely defined. Here, we reveal that lymphatic vessels in bone serve as dynamic orchestrators bridging inflammatory clearance with stromal fate determination during regeneration. Using lineage tracing in Lyve1-creERT2; tdTomato mice and genetic ablation approaches, we demonstrate that injury-induced lymphangiogenesis is essential for timely osteogenesis. Prior depletion of lymphatic endothelial cells (LECs) exacerbates inflammation and impairs bone regeneration following injury. Notably, we identify Lyve1highmacrophages as lymphatic endothelial-like cells capable of transdifferentiation following efferocytosis. Mechanistically, engulfment of apoptotic cells activates fatty acid β-oxidation, increasing acetyl-CoA level that drive histone acetylation at the Lyve1 and Vegfc promoters, thereby licensing the macrophages-to-LECs transition. During the remodeling phase, lymphatic vessels help maintain local lipid homeostasis. Lymphatic impairment during bone repair leads to accumulation of polyunsaturated fatty acid-containing phosphatidylethanolamines (PE-PUFAs), which stabilize PPARγ through ZDHHC4-mediated palmitoylation. This process blocks ubiquitin-proteasome degradation and skews LepR+ bone mesenchymal stromal cells (BMSCs) toward adipogenesis at the expense of osteogenesis. Age-related lymphatic insufficiency recapitulates this pathological cascade, manifesting as impaired drainage, systemic lipid dysregulation, and compromised bone quality. Collectively, our findings establish lymphatic vessels, reconstructed by macrophages-to-LECs transdifferentiation, as stage-specific niche that guides osteogenic-adipogenic fate decision of BMSCs through lymphatic drainage capacity in skeletal repair.

INSTRUMENT(S): Liquid Chromatography MS - alternating - reverse-phase

PROVIDER: MTBLS13645 | MetaboLights | 2026-01-17

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13645_LC-MS_alternating_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13645_LC-MS_alternating_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	s_MTBLS13645.txt	Txt

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Project description:Hematopoietic stem cells (HSCs) primarily reside in the bone marrow where signals generated by stromal cells regulate their self-renewal, proliferation, and trafficking. Endosteal osteoblasts and perivascular stromal cells including endothelial cells3, CXCL12-abundant reticular (CAR) cells, leptin-receptor positive stromal cells, and nestin-GFP positive mesenchymal progenitors have all been implicated in HSC maintenance. However, it is unclear if specific hematopoietic progenitor cell (HPC) subsets reside in distinct niches defined by the surrounding stromal cells and the regulatory molecules they produce. CXCL12 (stromal-derived factor-1, SDF-1) regulates both HSCs and lymphoid progenitors and is expressed by all of these stromal cell populations. Here, we selectively deleted Cxcl12 from candidate niche stromal cell populations and characterized the effect on HPCs. Deletion of Cxcl12 from mineralizing osteoblasts has no effect on HSCs or lymphoid progenitors. Deletion of Cxcl12 from osterix-expressing stromal cells, which includes CAR cells and osteoblasts, results in constitutive HPC mobilization and a loss of B lymphoid progenitors, but HSC function is normal. Cxcl12 deletion in endothelial cells results in a modest loss of long-term repopulating activity. Strikingly, deletion of Cxcl12 in nestin-negative mesenchymal progenitors using Prx1-Cre is associated with a marked loss of HSCs, long-term repopulating activity, HSC quiescence, and common lymphoid progenitors. These data suggest that osterix-expressing stromal cells comprise a distinct niche that supports B lymphoid progenitors and retains HPC in the bone marrow, while expression of CXCL12 from stromal cells in the perivascular region, including endothelial cells and mesenchymal progenitors, support HSCs. Total of three samples of two groups analyzed. Replica samples of CXCL12-abundant reticular (CAR) cells from two CXCL12-GFP knock-in mice and a combined sample of PDGFRa+ Sca+ CD45- lineage- cells from three Prx1-Cre Rosa26Ai9/+ Cxcl12gfp/+ mice were used and analyzed.

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Coupling Inflammatory Resolution to Osteogenesis: Lymphatic Vessels as Stage-specific Niche Regulators in Skeletal Healing

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