CXCL12 (SDF-1)

C-X-C motif chemokine ligand 12 (CXCL12), also known as stromal cell-derived factor 1 (SDF-1), is a small secreted chemokine and the dominant niche-retention and quiescence signal for hematopoietic stem cells (HSCs) in the bone marrow. It acts through two cognate receptors — the canonical G-protein-coupled receptor CXCR4 and the atypical decoy/scavenging receptor ACKR3 (also called CXCR7) — to regulate stem-cell trafficking, immune-cell homing, and tissue regeneration. In aging, loss of CXCL12 from the bone marrow niche, accumulation of CXCL12 as a senescence-associated secretory phenotype (SASP) factor in peripheral tissues, and dysregulation of the CXCL12–CXCR4 axis contribute to stem-cell-exhaustion, altered-intercellular-communication, and tissue deterioration.

Identity

UniProt: P48061 (SDF1_HUMAN) — Swiss-Prot, manually reviewed
NCBI Gene ID: 6387 (symbol: CXCL12)
HGNC: 10672
Ensembl: ENSG00000107562 (chromosome 10q11.21)
Mouse ortholog: Cxcl12 (one-to-one ortholog; P40224 SDF1_MOUSE; highly conserved function)
GenAge: no entry (CXCL12 is not in the curated HAGR aging gene set as of 2026-06-15; this is expected for a non-curated gene)
Protein length: 93 amino acids total (canonical/displayed isoform = SDF-1β, UniProt P48061-1); signal peptide residues 1–21; mature SDF-1β = residues 22–93 (72 aa); SDF-1α total = 89 aa (residues 90–93 are missing vs β), mature SDF-1α = residues 22–89 (68 aa)

Isoforms

CXCL12 is produced from a single gene (CXCL12, chromosome 10q11.21) but gives rise to at least seven isoforms (SDF-1α, SDF-1β, SDF-1γ, SDF-1δ, SDF-1ε, SDF-1θ, and isoform 7) generated by alternative splicing of the 3′ exons ¹. All isoforms share the N-terminal chemokine domain (containing the two canonical disulfide bonds and the CXCR4-binding interface); they differ in their C-terminal extensions, which vary in heparin-binding affinity and therefore spatial distribution in the extracellular matrix. SDF-1β is the canonical/displayed isoform in UniProt (P48061-1) and carries four additional C-terminal residues relative to SDF-1α (residues 90–93: RFKM), conferring higher heparin affinity and a more matrix-tethered distribution; both SDF-1α and SDF-1β are described as ubiquitously expressed (UniProt; ¹).

Key functional domains and post-translational modifications

Signal peptide (residues 1–21): cleaved co-translationally; mature forms begin at Lys22
Chemokine core (CXC motif): two N-terminal cysteines separated by a non-conserved residue; lacks the ELR tripeptide present in ELR+ CXC chemokines (e.g., CXCL8/IL-8), making CXCL12 non-angiogenic by the classical ELR rule, though it promotes vascular repair via progenitor-cell mobilization by an indirect mechanism
Two disulfide bonds: Cys30–Cys55 and Cys32–Cys71; essential for tertiary structure and receptor binding
N-terminal dipeptide cleavage by CD26 (DPP4): proteolytic removal of the first two residues (Lys–Pro) by dipeptidyl peptidase 4 (CD26) generates a truncated form with substantially reduced CXCR4 affinity (~1000-fold) but preserved ACKR3 binding; this N-terminal processing is a key in vivo regulatory mechanism that attenuates gradient signaling
Heparin-binding sites: Arg8, Arg12, Lys24, Lys27 within the N-loop; immobilize CXCL12 on heparan sulfate proteoglycans (HSPGs) in the extracellular matrix, creating steep concentration gradients and cell-surface-associated pools

Signaling via CXCR4 and ACKR3

CXCR4 — canonical G-protein pathway

CXCR4 (C-X-C motif receptor 4) is a class A G-protein-coupled receptor (GPCR) that couples primarily to Gαi proteins. Binding of CXCL12 to CXCR4 triggers:

Gαi signaling: inhibition of adenylyl cyclase → reduced cAMP; activation of phospholipase C-β → inositol trisphosphate (IP3) release → intracellular Ca²⁺ mobilization (transient rise within seconds of stimulation) ¹
PI3K–AKT axis: Gβγ subunits activate phosphoinositide 3-kinase (PI3K) → phosphatidylinositol-3,4,5-trisphosphate (PIP3) → AKT phosphorylation → cell survival and migration
MAPK cascade: Ras–Raf–MEK–ERK1/2 activation → proliferative and motility responses
β-arrestin recruitment: after receptor phosphorylation by G-protein receptor kinases (GRKs), β-arrestins dock, uncouple G-protein signaling, and mediate receptor internalization and endosomal signaling (distinct from G-protein outputs)

The net biological output is chemotaxis (directed migration toward CXCL12 gradients), enhanced adhesion to niche stromal cells, and pro-survival signaling. CXCR4 mutations in humans cause WHIM syndrome — warts, hypogammaglobulinemia, infections, myelokathexis — a combined immunodeficiency resulting from gain-of-function retention of neutrophils and B cells in bone marrow, underscoring the critical role of CXCR4 in hematopoietic-cell egress ¹. gap/needs-replication (human aging-specific CXCR4 signaling changes)

ACKR3/CXCR7 — atypical scavenging receptor

ACKR3 (atypical chemokine receptor 3, formerly CXCR7) binds CXCL12 with higher affinity than CXCR4 but has truncated intracellular loops that impair classical G-protein coupling. Its primary function is ligand scavenging: constitutive internalization and lysosomal degradation of CXCL12 ². Biological consequences:

Shape the CXCL12 gradient by acting as a sink, sharpening the chemotactic gradient sensed by CXCR4-expressing cells
Modulate CXCR4 surface expression through CXCL12-dependent internalization kinetics
Signal independently via β-arrestin in some cellular contexts (contested; may be cell-type-specific) ²

ACKR3 is prominently expressed on endothelial cells and in the developing nervous system; its scavenging function is essential for correct lymphatic and neural patterning during embryogenesis.

Role in the bone marrow HSC niche

CXCL12-abundant reticular (CAR) cells

The critical cellular source of niche CXCL12 is the CXCL12-abundant reticular (CAR) cell population — a subset of bone marrow mesenchymal stromal cells (also overlapping with leptin-receptor-positive, LepR+ cells) that express the highest levels of CXCL12 in the bone marrow ³. CAR cells form topologically complex reticular networks that pervade marrow tissue, maintain close contact with sinusoidal endothelial cells, and physically surround the HSC pool at both endosteal and perivascular locations ⁴. Their anatomy means that virtually all HSCs are within reach of CAR-cell-derived CXCL12.

Functional evidence (mouse): Induced deletion of Cxcr4 (the receptor for CXCL12) in adult mice resulted in severe reduction of HSC numbers and increased sensitivity to myelotoxic injury — establishing CXCL12-CXCR4 signaling as the dominant retention and quiescence-maintenance signal ³. The same study identified and named CAR cells as the primary stromal source of CXCL12 in both endosteal and perivascular niches. This work demonstrated that “CXCL12-CXCR4 signaling plays an essential role in maintaining the quiescent HSC pool” in defined stromal-cell niches.

Dimension	Status
Pathway conserved in humans?	yes — CXCL12, CXCR4, and CAR-cell equivalents all present in human bone marrow
Phenotype conserved in humans?	yes — CXCR4 antagonism (plerixafor) mobilizes HSCs in humans
Replicated in humans?	indirect — pharmacological evidence (plerixafor) is mechanistically confirmatory; no human genetic conditional deletion

Aging changes in the niche

With advancing age, the bone marrow niche undergoes progressive remodeling that impairs CXCL12 delivery to HSCs ⁵:

CAR-cell to adipocyte conversion: mesenchymal stromal cells — including CAR cells — progressively acquire adipogenic gene programs with age. This “yellow marrow” conversion reduces the density of CXCL12-secreting stromal cells and replaces them with adipocytes that provide a qualitatively different niche environment.
Vascular rarefaction: type H vessels (endosteal capillaries co-expressing CD31 and Endomucin), which associate with endosteal HSC niches, are reduced in aged bone marrow along with their PDGFRβ+ perivascular cells, lowering cellular SCF and further disrupting spatial CXCL12 gradients ⁶. Endothelial Notch or PDGF-B manipulation can partially rebuild this aged vascular niche, but cell-intrinsic HSC damage is not reversed by niche restoration alone ⁶.
CAR-cell senescence: a 2025 study demonstrated that chemotherapy triggers senescence in bone marrow adipocytes and CAR cells, and that senescent CAR cells produce SASP factors (including RANKL) that drive osteoclastogenesis and bone loss; elimination of senescent CAR cells with senolytics (dasatinib + quercetin) prevented this bone loss ⁷. Whether physiological aging produces the same CAR-cell senescence is an active question. gap/needs-human-replication
Lymphatic-endothelial CXCL12 (injury-inducible source): beyond CAR cells and sinusoidal endothelium, bone lymphatic endothelial cells are a newly-recognized CXCL12 source. After genotoxic stress they expand and secrete CXCL12 to drive HSC regeneration (and signal a MYH11+ perivascular progenitor population for bone repair); in aged bone these lymphatic endothelial cells turn senescent and fail to expand, so this regenerative CXCL12 pulse is lost — a defect rescued by young-LEC transfer ⁸. See prox1, lyve1.

Net effect: aged HSCs experience reduced CXCL12-mediated retention signals, shifting the balance toward mobilization and activation. Paradoxically, aged HSCs expand in number while declining in per-cell reconstitution capacity — a pattern consistent with chronic, low-level activation and proliferative exhaustion rather than quiescence maintenance. The CXCL12 gradient attenuation is one candidate driver of this phenotype.

Clinical pharmacology: plerixafor (AMD3100)

Plerixafor (AMD3100; trade name Mozobil) is a bicyclam small molecule that competitively antagonizes CXCL12 binding to CXCR4, pharmacologically disrupting HSC retention in bone marrow and mobilizing them into peripheral blood ⁹. It is FDA-approved in combination with granulocyte-colony-stimulating factor (G-CSF) for autologous HSC mobilization before transplantation in patients with non-Hodgkin’s lymphoma and multiple myeloma.

Plerixafor’s clinical use provides proof-of-concept that the CXCL12–CXCR4 axis is therapeutically tractable for modulating HSC bone-marrow egress in humans — but no current clinical application targets this axis for an aging indication. The aging-context druggability tier reflects this: tier 2 (high-quality clinical probe exists, but not validated for aging indication). See § Aging-context druggability below.

Role in muscle regeneration

CXCL12 and CXCR4 are expressed by skeletal muscle cells and resident progenitors, including satellite cells (muscle stem cells) and their progeny myoblasts. The chemokine promotes muscle repair through two complementary mechanisms:

Progenitor-cell recruitment: CXCL12 gradients at the site of muscle injury mobilize CXCR4+ and CD34+ progenitors (including circulating hematopoietic progenitors and bone-marrow-derived cells) into regenerating muscle, augmenting the resident satellite-cell response ¹⁰. SDF-1 infusion in injured muscle increased the number of CXCR4+ cells at the repair site, enhanced metalloprotease activity, and improved myofiber regeneration metrics in rodent models.
Angiogenesis during repair: CXCL12 binding to extracellular matrix via its heparin-binding domain is “crucial for proper muscle regeneration,” particularly by supporting angiogenesis during severe tissue injury ¹¹. Cxcl12 mutant mice with impaired heparan-sulfate binding show defective vascular support during muscle repair, resulting in poor regeneration outcomes.

Aging relevance: No published study has directly characterized age-related CXCL12 changes in the skeletal-muscle niche specifically. Given that satellite-cell niche aging involves altered systemic and local signaling (see satellite-cells), CXCL12 dysregulation in the muscle microenvironment represents a plausible but uncharacterized contributor to impaired regeneration in aged muscle. The secondary CXCL12_22 locus on the dnam-muscle-function-markers page (hypomethylated in sarcopenic adults; validated in one set only) provides indirect evidence that CXCL12 gene regulation is associated with muscle function decline in humans, but the mechanistic interpretation is speculative. gap/no-mechanism gap/needs-human-replication

Role in senescence and SASP

CXCL12 is increasingly recognized as a component of the senescence-associated secretory phenotype (SASP). Multiple studies have detected elevated CXCL12 in SASP profiles from distinct cell types:

Radiation-induced senescent prostate stromal cells: upregulate CXCL12 in their secretome, promoting proliferative and survival signaling (ERK1/2, AKT, STAT5) in neighboring non-senescent cells ¹²
Autophagy-deficient senescent melanocytes: SASP includes elevated CXCL12, CXCL1, CXCL2, and CXCL10 ¹³
Senescent endothelial cells (vascular aging): a 2026 peer-reviewed study demonstrated that aged (but not young) endothelial cells express elevated CXCL12; fisetin senolytic treatment (100 mg/kg/day, intermittent) in aged C57BL/6 mice (both sexes, 27 months) reduced endothelial senescence, normalized circulating CXCL12, and improved ex vivo vascular function, with CXCL12 identified as a partial mediator of the vascular aging phenotype — acting via promotion of mitochondrial oxidative stress, reduced nitric oxide bioavailability, and vascular inflammation ¹⁴. This is the most direct evidence linking CXCL12-SASP to aging-associated vascular dysfunction.
Senescent hepatic fibroblasts: a multi-omic human liver study identified CXCL12+ senescent fibroblasts in fibrotic regions interacting with CXCR4+ immune cells, suggesting a paracrine loop that maintains inflammatory microenvironments in aging liver ¹⁵

CXCL12 in the SASP context likely drives paracrine CXCR4 signaling in neighboring immune and stromal cells, recruiting CXCR4+ inflammatory cells and promoting local chronic inflammation — contributing to inflammaging and altered-intercellular-communication. This is mechanistically distinct from the niche-retention function in bone marrow, where CXCL12 maintains quiescence. The divergence reflects cell-type specificity: the same secreted signal maintains stem-cell quiescence in the bone marrow niche and promotes immune cell infiltration and inflammation in peripheral tissues.

Dimension	Status
CXCL12 as SASP factor conserved in humans?	yes — multi-cell-type evidence in human and mouse
Phenotype (aging tissue inflammation via CXCL12-SASP) conserved?	partial — vascular evidence is peer-reviewed mouse data (Mahoney 2026 Aging Cell); liver evidence is multi-omic/exploratory human data
Replicated in humans via interventional studies?	no — senolytic reduction of CXCL12 in vascular aging is preclinical (mouse, Mahoney 2026); plasma exposure experiments with human aortic ECs provide mechanistic cross-species support

Pathway membership

cxcl12-cxcr4-pathway (stub) — canonical niche-retention and stem-cell-trafficking axis; CXCL12 is the primary ligand
chemokine-signaling (stub) — broader chemokine receptor-signaling context
pi3k-akt-pathway — downstream of CXCR4 Gβγ subunit; promotes survival
mapk-pathway — ERK1/2 branch downstream of CXCR4; promotes motility and proliferation

Key interactors

cxcr4 (stub) — primary signaling receptor; coupling to Gαi, PI3K, MAPK, and β-arrestin pathways; targeted by plerixafor
ackr3 (stub) — atypical receptor; scavenging/gradient-shaping; independent β-arrestin signaling contested
cd44 — CXCL12 can potentiate CD44-mediated adhesion; relevant to HSC niche anchoring
heparan-sulfate-proteoglycans (stub) — matrix-immobilization; essential for chemotactic gradient formation; disrupted in aged extracellular matrix
mmp-2 (stub) — can cleave CXCL12 locally, fine-tuning gradient dynamics during tissue repair

Pharmacology and aging-context druggability

Aging-context tier 2 rationale. The CXCL12–CXCR4 axis is clinically tractable: plerixafor (AMD3100) is FDA-approved as a CXCR4 antagonist for HSC mobilization (non-Hodgkin’s lymphoma and multiple myeloma autologous transplant). This establishes a high-quality clinical probe. However, no drug currently targets CXCL12 or CXCR4 for an aging indication — not HSC quiescence restoration, sarcopenia, senescence clearance, or vascular rejuvenation. The clinical literature in aging contexts is observational and preclinical. Tier 2 (high-quality probe, not aging-validated) is therefore correct; tier 1 would require a drug that engages this protein for an aging-relevant indication in validated clinical trials.

Potential aging-therapeutic strategies (all preclinical or conceptual):

Restore bone marrow CXCL12 gradients — rather than antagonize CXCR4, delivering or inducing CXCL12 in aged bone marrow to restore niche-retention signals and HSC quiescence; no clinical-stage agent.
Modulate SASP-CXCL12 — senolytics (fisetin, dasatinib + quercetin) that reduce senescent-cell burden secondarily reduce CXCL12-SASP secretion; the vascular evidence (Mahoney et al. 2026, Aging Cell, peer-reviewed) demonstrates this in aged mice and in plasma-exposure experiments with human aortic endothelial cells. See fisetin and dasatinib.
CXCR4 agonism / partial agonism — targeted niche-retention or HSC quiescence enhancement; no clinical compound exists with this pharmacological profile.
CXCL12 isoform-specific targeting — isoform δ and γ variants are enriched in neural tissues; isoform-selective tools are research-only.

Aging-context causal evidence

mr-causal-evidence: not-tested — No Mendelian randomization study has used genetic instruments for CXCL12 expression/secretion to test causal effects on aging outcomes (HSC function, sarcopenia, vascular aging, or lifespan). Genetic instruments are available via expression quantitative trait loci (eQTLs) for CXCL12 in GTEx, making this feasible. gap/needs-replication (MR study of CXCL12 → aging outcomes)

Limitations and gaps

Niche vs. SASP dichotomy mechanistically unresolved. CXCL12 maintains HSC quiescence in bone marrow yet drives inflammation when secreted as SASP in peripheral tissues. The cell-type and context determinants of this opposite functional polarity are not fully characterized. Whether aging-associated shifts in CXCL12 source cells (e.g., CAR → senescent fibroblast) are the key driver of pathological SASP-CXCL12 accumulation is not established. gap/no-mechanism
Muscle aging CXCL12 changes uncharacterized. The CXCL12_22 DMR on the dnam-muscle-function-markers biomarker page is a blood methylation signal that validated only in set 1 of the Li 2024 study. No study has directly measured CXCL12 protein in the aged skeletal-muscle niche or characterized its relationship to satellite-cell function. gap/needs-human-replication
Aging-specific CXCR4 pharmacology untested. Despite plerixafor’s clinical validation for HSC mobilization, no trial has tested whether modulating CXCR4 signaling improves age-related HSC dysfunction, sarcopenia, or vascular aging. gap/long-term-unknown
CD26/DPP4 truncation in aging unknown. CD26 (DPP4) activity changes with metabolic and inflammatory aging; whether enhanced DPP4-mediated truncation of CXCL12 in aged individuals impairs CXCR4 signaling is not studied. DPP4 inhibitors (gliptins, used for type 2 diabetes) might incidentally preserve CXCL12 activity — this interaction is uncharacterized in aging. gap/no-mechanism
Human aging niche evidence limited. Most niche-CXCL12 data are from mouse models. Human bone marrow aging studies using quantitative 3D microscopy (as in Gomariz 2018) have not specifically measured CAR-cell density and CXCL12 secretory capacity across decades of human aging. gap/needs-human-replication
ACKR3/CXCR7 aging expression not characterized. How ACKR3 expression changes with age in endothelial cells or other SASP-relevant cell types, and whether its scavenging function degrades with cellular senescence, is unknown. gap/needs-replication

Footnotes

doi:10.1016/j.cyto.2017.12.022 · PMID 29398278 · Murphy PM, Heusinkveld L · Cytokine 2018;109:2–10 · review · model: human/mouse literature synthesis · multisystem roles of CXCL12/CXCR4/ACKR3 including G-protein signaling (Gαi, PLC-β, PI3K, MAPK, β-arrestin), WHIM syndrome, and isoform biology ↩ ↩² ↩³ ↩⁴
doi:10.1124/molpharm.120.000056 · PMID 32883765 · Koch C, Engele J · Mol Pharmacol 2020;98(5):577–585 · review · model: human/mouse cell biology literature · ACKR3/CXCR7 functions as a scavenger receptor shaping CXCL12 gradients and modulating CXCR4 signaling; independent β-arrestin signaling capability is cell-type-dependent and debated ↩ ↩²
doi:10.1016/j.immuni.2006.10.016 · PMID 17174120 · Sugiyama T, Kohara H, Noda M, Nagasawa T · Immunity 2006;25(6):977–988 · in-vivo (mouse, inducible Cxcr4 deletion in adult mice) · model: C57BL/6; inducible CXCR4-knockout · induced deletion of CXCR4 in adult mice caused severe reduction of HSC numbers and increased sensitivity to myelotoxic injury; CAR cells identified and named as the primary stromal source of CXCL12 in both endosteal and perivascular niches; established that CXCL12-CXCR4 signaling is essential for maintaining the quiescent HSC pool · closed-access gap/no-fulltext-access ↩ ↩²
doi:10.1038/s41467-018-04770-z · PMID 29955044 · Gomariz A et al. · Nat Commun 2018;9:2532 · observational (3D quantitative microscopy, mouse bone marrow) · model: C57BL/6 mice young vs aged · CXCL12-abundant reticular cells form complex networks pervading marrow; structural architecture preserved during aging but density and CXCL12 output not directly quantified at the protein level in this study ↩
doi:10.1016/j.exphem.2025.104749 · PMID 39978750 · Nakatani T, Nagasawa T · Exp Hematol 2025;144:104749 · review · model: mouse/human aging literature · CAR-cell/LepR+ MSC conversion to adipocytes, vascular rarefaction of type H vessels, and niche senescence as aging-associated changes impairing HSC maintenance; senolytics as a candidate countermeasure ↩
kusumbe-2016-vascular-niche-aging · doi:10.1038/nature17638 · Kusumbe AP, Ramasamy SK, Itkin T, … Adams RH · Nature 2016 · in-vivo (mouse, C57BL/6J; young 2–5 wk, aged 55–70 wk) · age decline of type-H endothelium + PDGFRβ+/NG2+ perivascular cells reduces cellular SCF and HSC support (P<0.0001); endothelial Notch (Fbxw7) GOF or PDGF-B overexpression partially restores niche + HSC frequency; cell-intrinsic HSC aging (γH2AX) not rescued by niche rejuvenation · verified 2026-06-28 ↩ ↩²
doi:10.1038/s41467-025-67793-3 · PMID 41469373 · PMC12848019 · Raut GK, Malachowski T, Melam A, Ramalho-Oliveira R, … Stewart SA · Nat Commun 2025;17(1):1042 · in-vivo (mouse, chemotherapy-induced bone marrow niche senescence) · model: C57BL/6 mice, chemotherapy-treated; dasatinib+quercetin senolytic arm · chemotherapy induces senescence selectively in CAR cells and bone marrow adipocytes; senescent CAR cells produce SASP including RANKL, driving osteoclastogenesis and bone loss; p38MAPK-MK2 inhibition suppresses SASP; D+Q senolytics selectively eliminate senescent CAR cells and prevent bone loss; CXCL12 reduction not specifically quantified — RANKL is the key SASP mediator characterized in this study ↩
biswas-2023-bone-lymphatics · doi:10.1016/j.cell.2022.12.031 · Biswas L, Chen J, De Angelis J, … Kusumbe AP · Cell 2023;186:382–397 · in-vivo (mouse) + human bone biopsy · bone LYVE1+/PROX1+/VEGFR3+ lymphatic endothelial cells secrete CXCL12 after genotoxic stress (irradiation, 5-FU) to drive HSC regeneration + MYH11+ perivascular progenitor expansion; aged bone LECs senescent and fail to expand; young-LEC transfer rescues · verified end-to-end 2026-06-28 ↩
doi:10.1592/phco.30.5.485 · PMID 20411999 · Kessans MR, Gatesman ML, Kockler DR · Pharmacotherapy 2010;30(5):485–492 · review (clinical pharmacology) · model: human clinical trial and pharmacological literature · plerixafor competitively antagonizes CXCR4-SDF-1α binding, mobilizing HSCs into peripheral blood; FDA-approved with G-CSF for NHL and myeloma autologous transplantation ↩
doi:10.1111/boc.201200022 · PMID 22978573 · Brzoska E et al. · Biol Cell 2012;104(12):722–737 · in-vivo + in-vitro (mouse, muscle injury model) · model: mouse tibialis anterior injury; C57BL/6 · SDF-1 mobilizes CXCR4+ and CD34+ stem/progenitor cells to injured muscle; enhances myoblast migration and metalloprotease activity; improved muscle regeneration metrics ↩
doi:10.1186/s13395-019-0210-5 · PMID 31533830 · Hardy D, Fefeu M, Besnard A, Briand D, … Chrétien F · Skeletal Muscle 2019;9:25 · in-vivo (mouse, Cxcl12 heparin-binding mutant) · model: Cxcl12 HBD-mutant vs wild-type mice; tibialis anterior injury · heparin-sulfate binding of CXCL12 is required for proper angiogenesis and muscle regeneration post-injury; mutant mice showed impaired vascular repair and reduced myofiber regeneration ↩
doi:10.1096/fba.2018-00084 · PMID 31844843 · Jiang S, Song CS, Chatterjee B · FASEB Bioadv 2019;1(6):353–363 · in-vitro (human prostate epithelial and stromal cells, radiation-induced senescence) · model: human prostate epithelial (BPH-1, PNT-1α) and stromal (HPS-19I) cell lines · radiation-induced senescent prostate cells upregulate CXCL12 (among other SASP components: IL-1α, IL-6, IL-8, GM-CSF, MMPs); conditioned media from senescent cells activates ERK1/2, AKT, STAT5 in non-senescent cells; CXCL12 as a SASP-mediated paracrine signal ↩
doi:10.1016/j.biocel.2016.10.006 · PMID 27732890 · Ni C et al. (Gruber F corr. author) · Int J Biochem Cell Biol 2016;81(Pt B):375–382 · in-vitro (mouse Atg7-knockout melanocytes, autophagy-deficiency model) · Atg7-deficient mouse melanocytes display SASP including elevated Cxcl12, Cxcl1, Cxcl2, Cxcl10 alongside pro-inflammatory gene signature and elevated MMP-3/MMP-13; oxidized lipid mediators proposed as DAMP-type SASP components ↩
doi:10.1111/acel.70500 · PMID 42021544 · PMC13103471 · Mahoney SA, Mazan-Mamczarz K, Tsitsipatis D, VanDongen NS, … Clayton ZS · Aging Cell 2026;25(5):e70500 · in-vivo + ex-vivo (aged mouse, fisetin senolytic treatment; human aortic EC plasma-exposure validation) · model: aged C57BL/6 mice (27 mos, both sexes) vs young (6 mos); fisetin 100 mg/kg/day intermittent; isolated mouse arteries + human aortic ECs in plasma exposure experiments · senescent endothelial cells exhibited elevated Cxcl12; fisetin reversed endothelial Cxcl12 expression and reduced circulating CXCL12; plasma from old mice impaired endothelial function via CXCL12-driven mitochondrial oxidative stress, reduced NO, and endothelial-to-mesenchymal transition; these effects were prevented by fisetin · Peer-reviewed (originally posted as bioRxiv 2025 doi:10.1101/2025.08.13.670216) ↩
doi:10.1016/j.xgen.2025.101133 · PMID 41576948 · Karpova A, Li X, Peng CW, Gallant KL, … Ding L · Cell Genomics 2026;6(2):101133 · observational multi-omic (human liver, aging + cancer) · model: human liver tissue samples across age and disease stages · CXCL12+ senescent fibroblasts in fibrotic liver regions interact with CXCR4+ immune cells; identifies senescent-cell CXCL12 as part of fibrotic/inflammatory microenvironment in aging human liver ↩

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