Idiopathic pulmonary fibrosis (IPF) remains one of the most recalcitrant diseases in respiratory medicine. The two approved antifibrotics, nintedanib and pirfenidone, slow decline but neither halts nor reverses fibrotic remodeling in the lung parenchyma. Median survival sits at three to five years from diagnosis. Against this backdrop, mesenchymal stromal cell (MSC)-based therapies have entered a decisive translational phase: multiple completed and actively recruiting clinical trials now test intravenous, intrabronchial, and nebulized MSC products head-to-head against standard care. This review synthesizes the latest preclinical evidence, mechanism-of-action data, and trial pipeline to give the practicing pulmonologist or translational researcher a clear picture of where MSC therapy for pulmonary fibrosis stands in late 2026.

Preclinical Evidence: A Meta-Analytic Signal

Jabeen et al. published the most comprehensive systematic review and meta-analysis to date of adipose-derived MSC (AD-MSC) strategies in preclinical pulmonary fibrosis models (European Journal of Pharmacology, 2026). Screening 397 records down to 19 qualifying studies, the team pooled Ashcroft fibrosis scores using a random-effects model. The overall mean difference was -1.35 (95% CI: -3.19 to 0.49), which did not reach statistical significance (z = 1.44, p = 0.15), likely driven by small study numbers and substantial heterogeneity across cell preparations and delivery routes. However, individual studies consistently demonstrated reduced fibrosis in treated groups versus controls.

Importantly, the review identified four dominant antifibrotic pathways modulated by AD-MSCs: the Smad2/3 signaling axis (the canonical TGF-beta effector cascade), NF-kB-dependent inflammatory amplification, ERK-mediated fibroblast proliferation, and key miRNA networks governing extracellular matrix turnover. These pathways converge on the central fibrotic machinery in IPF, positioning AD-MSCs as multi-target antagonists rather than single-pathway inhibitors. The PROSPERO-registered protocol (CRD420251119193) and use of SYRCLE’s risk-of-bias tool add methodological rigor that earlier narrative reviews lacked.

Engineered MSCs: Immune Cloaking for Persistent Fibrosis

One barrier to MSC persistence in fibrotic lungs is rapid clearance by tissue-resident alveolar macrophages. Cho et al. addressed this directly in Современные материалы (2026) by coating MSCs with soft conformal microgels functionalized with the CD47 self-marker agonist. CD47 acts as a “don’t eat me” signal on cell surfaces, engaging the macrophage receptor SIRP-alpha to suppress phagocytosis.

In murine models of persistent pulmonary fibrosis, these immune-cloaked MSCs survived significantly longer in the lung than uncoated controls. Single-cell RNA sequencing revealed a transitional antigen-presenting macrophage subpopulation that mediated the reparative effects through paracrine signaling. The engineered MSCs reversed established fibrotic damage, not merely prevented its progression. This “living pharmacy” concept, where coated secretory cells persist long enough to deliver sustained therapeutic payloads, represents a meaningful engineering advance over first-generation MSC infusions that are cleared within hours.

Extracellular Vesicles: Nebulized Delivery and miRNA Cargo

Cell-free approaches using MSC-derived extracellular vesicles (EVs) sidestep many safety concerns associated with live cell administration (tumorigenicity, embolism risk, immunogenicity). Two recent studies demonstrate the maturation of this platform.

Wang et al. established a GMP-grade manufacturing process for umbilical cord MSC-derived small EVs (UC-sEVs) and characterized their cargo via RNA sequencing (Stem Cell Reviews and Reports, 2026). The dominant therapeutic effector was miR-146a-5p, which targets the TRAF6/IRAK1 axis to suppress NF-kB-driven inflammatory cascades. In the bleomycin-induced IPF mouse model, nebulized UC-sEVs reduced pulmonary inflammation by reprogramming macrophage polarization and attenuated subsequent fibrotic progression. Crucially, the authors demonstrated batch-to-batch consistency across three GMP production runs, with highly similar miRNA expression profiles. They propose miR-146a-5p enrichment as a release criterion, a concrete quality attribute that clinical manufacturers can adopt.

Ashtari et al. took a complementary approach, comparing inhalation versus systemic injection of AD-MSC exosomes at two dose levels in bleomycin-treated Wistar rats (Artificial Organs, 2026). The inhalation route produced superior outcomes at both doses (250 and 500 microg/kg), with significant reductions in CRP, fibrinogen, pro-inflammatory cytokines, and histopathological fibrosis scores compared to intravenous delivery (p < 0.05). This head-to-head delivery route comparison, uncommon in the literature, provides direct evidence supporting nebulized or bronchoscopic administration for IPF patients.

The Gut-Lung Axis: A New Mechanism for Radiation-Induced Fibrosis

Radiation-induced pulmonary fibrosis (RIPF) affects cancer survivors who received thoracic radiotherapy and shares pathological features with IPF. Zhou et al. demonstrated that human UC-MSC exosomes attenuate RIPF through remodeling of the gut-lung axis (Life Sciences in Space Research, 2026). Multi-omics analysis combining metagenomics and untargeted metabolomics revealed that exosome treatment restored gut microbiota homeostasis and reprogrammed intestinal metabolic profiles. L-Glutamic acid emerged as the most significantly altered metabolite and correlated positively with fibrosis severity. The alanine, aspartate, and glutamate pathway was co-regulated. This finding expands the therapeutic mechanism beyond direct antifibrotic action at the lung and suggests that MSC-derived EVs may work partly by repairing the intestinal barrier, reducing systemic inflammation that fuels pulmonary scarring.

Clinical Trial Pipeline: Completed and Recruiting

The clinical translation of MSC therapy for IPF has accelerated markedly. The following trials provide the most relevant near-term data:

• NCT05468502 (Phase I/IIa, COMPLETED): Human umbilical cord MSC injection for IPF, conducted in China. This trial evaluated safety and preliminary efficacy of systemic UC-MSC delivery. Results are pending publication.
• NCT06230822 (Phase I, COMPLETED): VUM02 injection, a characterized allogeneic MSC product, tested for safety and tolerability in IPF patients. Completed in 2024.
• NCT07131150 (Phase 2, NOT YET RECRUITING): SC01009, a menstrual blood-derived MSC injection, targeting IPF with an anticipated start in late 2025. This is the first trial to use menstrual blood as an MSC source for pulmonary indications.
• NCT07515066 (Phase 1, NOT YET RECRUITING): Nebulized 3D-cultured human placental MSC-derived extracellular vesicles for IPF. Planned start May 2026. This trial directly translates the preclinical nebulized EV evidence described above.

The pipeline now spans intravenous MSC injection, nebulized EVs, and novel tissue sources (menstrual blood, placental tissue). The NCT07515066 trial is particularly noteworthy because it combines the nebulized delivery route that Ashtari et al. showed was superior to injection, with 3D-cultured cell-derived EVs that typically carry higher cargo loads than conventional 2D culture products.

Delivery Route Considerations

Intravenous MSCs pass through the pulmonary vasculature, where a “pulmonary trap” effect causes entrapment and rapid clearance. Intrabronchial instillation targets the airways directly but requires bronchoscopy. Nebulized delivery offers a non-invasive outpatient alternative. Ashtari et al.’s direct comparison showing better efficacy with inhalation, combined with the NCT07515066 nebulized EV trial, suggest that inhalational delivery may become the preferred route for EV-based MSC therapies in IPF.

Safety Profile Across Trials

The early-phase trials (NCT01385644, NCT02013700) established baseline safety for IV MSC delivery in IPF patients, though the AETHER trial (NCT02013700) was terminated for strategic rather than safety reasons. The completed NCT05468502 and NCT06230822 trials will provide updated safety data from more recent MSC products with better characterized release criteria. Cell-free EV approaches eliminate the theoretical risks of ectopic tissue formation, pulmonary embolism from cell aggregation, and immunogenic rejection of allogeneic cells, making them attractive for the fragile IPF population.

Remaining Questions and Future Directions

Several critical questions persist. First, which MSC tissue source provides the best antifibrotic potency? Jabeen et al.’s meta-analysis focused on AD-MSCs, but the clinical trials predominantly use umbilical cord or placental MSCs. Second, the optimal dosing schedule remains undefined. Third, miR-146a-5p enrichment as a release criterion needs validation in independent pipelines. Fourth, whether gut-targeted interventions could enhance EV efficacy is untested. Finally, Cho et al.’s immune-cloaking approach could transform the persistence problem that has plagued systemic MSC delivery.

The field is converging on a view that MSC-derived EVs, particularly nebulized products with defined miRNA cargo, will likely outpace whole-cell therapies for IPF. The completed Phase I/IIa trials and the actively recruiting nebulized EV trial (NCT07515066) will produce the efficacy signals needed to design Phase III studies. For practicing clinicians, the near-term practical question is which IPF patients to refer for trial enrollment, and the answer, based on current evidence, is those with early-to-moderate disease (FVC > 50% predicted) who have not yet progressed to oxygen dependence.

Frequently Asked Questions

Is MSC therapy approved for IPF anywhere in the world?

No regulatory agency has approved MSC therapy for IPF as of September 2026. All current use is within clinical trials or compassionate-use frameworks. The two approved antifibrotics for IPF remain nintedanib and pirfenidone.

How do MSC-derived EVs differ from stem cell injections?

EVs are nanoscale membrane vesicles (30 to 150 nm) secreted by MSCs. They carry proteins, lipids, and RNA cargo (including miRNAs) that recapitulate many paracrine effects of the parent cells without introducing live cells into the patient. This eliminates risks of ectopic tissue formation and reduces immunogenicity.

Why does delivery route matter so much?

Intravenous delivery causes most MSCs or EVs to be trapped in the pulmonary vasculature and cleared rapidly. Nebulized delivery targets the airways and alveolar epithelium directly, achieving higher local concentrations with lower systemic exposure. Ashtari et al. showed inhalation was superior to injection for reducing fibrosis markers in a direct comparison.

Can MSC therapy reverse existing fibrosis or only slow progression?

Cho et al.’s immune-cloaked MSC study showed reversal of established fibrosis in mice, which is a stronger claim than merely slowing progression. However, this has not been demonstrated in human IPF patients yet. Current clinical trials measure FVC decline rate (a slowing endpoint), not fibrosis reversal on imaging.

What is the gut-lung axis and why does it matter for IPF?

The gut-lung axis refers to the bidirectional communication between intestinal microbiota and pulmonary immune function. Zhou et al. showed that UC-MSC exosomes repaired gut barrier integrity, restructured gut microbiota, and reduced L-Glutamic acid levels that correlated with fibrosis severity. This suggests that EVs may work partly by treating systemic inflammation originating from gut dysbiosis.

Who is a candidate for MSC IPF clinical trials?

Eligibility varies by trial, but generally patients with diagnosed IPF (per ATS/ERS guidelines), early-to-moderate disease (FVC > 50% predicted), and stable antifibrotic therapy qualify. Patients on immunosuppressants, those with active malignancy, or those requiring supplemental oxygen may be excluded. Check ClinicalTrials.gov for specific trial criteria.

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использованная литература

• Jabeen H, Ali M, Anum F, et al. Antifibrotic efficacy of adipose-derived mesenchymal stem cell-based therapeutic strategies in pre-clinical models of pulmonary fibrosis: A systematic review and meta-analysis. Eur J Pharmacol. 2026;1027:178959. doi:10.1016/j.ejphar.2026.178959
• Cho IS, Yaghmour A, Joshi A, et al. Innate Immune-Cloaked Microgel-Coated Mesenchymal Stromal Cells Reverse Persistent Pulmonary Fibrosis via Reparative Macrophages. Adv Mater. 2026;38(1):e04590. doi:10.1002/adma.202504590
• Wang X, Meng L, Wang Q, et al. Investigating the Therapeutic Efficacy of Quality-Controlled, miR-146a-5p-Enriched Small Extracellular Vesicles Derived From MSCs Against Idiopathic Pulmonary Fibrosis. Stem Cell Rev Rep. 2026;22(1):523-544. doi:10.1007/s12015-025-10976-8
• Ashtari A, Radan M, Dayer D, et al. Adipocyte Mesenchymal Stem Cells Derived Exosomes Improve Bleomycin-Induced Lung Fibrosis in Rat. Artif Organs. 2026;50(3):381-392. doi:10.1111/aor.70052
• Zhou Y, Wang H, Guo L, et al. Human umbilical cord MSC-derived exosomes attenuate radiation-induced pulmonary fibrosis via remodeling the gut-lung axis in mice. Life Sci Space Res. 2026;48:204-215. doi:10.1016/j.lssr.2025.11.011