Harnessing CD146-positive mesenchymal stromal cells for precision therapy in acute respiratory distress syndrome

Abstract

Acute respiratory distress syndrome (ARDS) is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options. Notably, Zhang et al demonstrated that CD146+ mesenchymal stromal cells (MSCs) exhibited greater therapeutic efficacy than CD146- MSCs. These cells enhance epithelial repair through nuclear factor kappa B/cyclooxygenase-2-associated paracrine signaling and secretion of pro-angiogenic factors. We concur that MSCs hold significant promise for ARDS treatment; however, the heterogeneity of cell products is a translational barrier. Phenotype-aware strategies, such as CD146 enrichment, standardized potency assays, and extracellular vesicle profiling, are essential for improving the consistency of these studies. Furthermore, advanced preclinical models, such as lung-on-a-chip systems, may provide more predictive insights into the therapeutic mechanisms. This article underscores the importance of CD146+ MSCs in ARDS, emphasizes the need for precision in defining cell products, and discusses how integrating subset selection into translational pipelines could enhance the clinical impact of MSC-based therapies.

Key Words: Acute respiratory distress syndrome; Mesenchymal stromal cells; CD146; Nuclear factor kappa B/cyclooxygenase-2 signaling pathway; Extracellular vesicles; Endothelial barrier repair; Precision medicine

Core Tip: Acute respiratory distress syndrome remains a major significant clinical challenge for translational researchers because of its high mortality and paucity of effective therapies. Mesenchymal stromal cells (MSCs) represent a promising approach for immunomodulation and barrier repair. However, heterogeneity within cell populations results in variable clinical efficacies. This editorial endorses the study by Zhang et al, which highlighted the greater therapeutic efficacy of the CD146+ MSC subpopulation through nuclear factor kappa B-mediated paracrine regulation. Furthermore, the authors highlighted future directions, including phenotype-focused manufacturing, multi-marker integration, and cell-free therapies based on extracellular vesicles or secretomes, illustrating the potential of MSC-based interventions for precision medicine.

INTRODUCTION

Acute respiratory distress syndrome (ARDS) continues to present a critical clinical challenge because of its high mortality rate and limited availability of disease-modifying treatments[1]. Although mesenchymal stromal cells (MSCs) provide a biological rationale for their immunomodulatory and barrier repair capabilities, inconsistencies in clinical outcomes remain a significant obstacle[2,3]. A primary factor contributing to this inconsistency is the functional heterogeneity of MSCs, which is influenced by their source and microenvironment[2,4]. A study conducted by Zhang et al[5] offers a compelling solution to this issue by presenting evidence that varying culture conditions significantly alter the therapeutic efficacy of MSCs, with the most effective medium (YF, cell culture medium: a proprietary medium supplied by Shandong Qilu Cell Therapy Engineering Technology Co. Ltd. enriching the CD146+ subpopulation. In essence, the study highlighted by Zhang et al[5] suggests that the CD146+ subpopulation demonstrates higher therapeutic efficacy than CD146- cells, indicating that a precision cell therapy approach based on selecting the “right phenotype” may be more rational for ARDS. This framework reinforces the clinical-translational message that the future of MSC therapies should prioritize “cell identity rather than cell number”[6,7].

MECHANISTIC BASIS FOR THE SUPERIORITY OF CD146+ CELLS: THE CD146/ NUCLEAR FACTOR KAPPA B/CYCLOOXYGENASE-2 AXIS AND PARACRINE DOMINANCE

The study showed that CD146+ MSCs activate the nuclear factor kappa B (NF-κB) pathway more effectively than CD146- cells, leading to increased cyclooxygenase-2 (COX-2) expression and subsequently triggering the secretion of pro-angiogenic and immunomodulatory factors [hepatocyte growth factor (HGF), prostaglandin E2 (PGE2), angiopoietin-1 (Ang-1), and vascular endothelial growth factor (VEGF)] (Figure 5D and E in the original article)[5]. This mechanism accounts for the enhanced secretion of paracrine factors (Figure 3B in the original article) and T-cell modulation [suppression of type 1 helper T (Th1)/Th17 and induction of regulatory T (Tregs)] (Figure 3D in the original article)[5]. Numerous studies have also consistently reported that CD146+ MSCs robustly activate the NF-κB pathway, thereby enhancing COX-2 expression and secretion of trophic factors such as PGE2, VEGF, HGF, and Ang-1 (Figure 5D and E in the original article)[5,6]. These findings are summarized in Table 1 and supported by both the direct data of the study and the existing literature.

Table 1 Comparative summary of CD146- and CD146+ mesenchymal stromal cells in acute respiratory distress syndrome.

Parameter	CD146- MSCs	CD146+ MSCs	Literature-based clinical perspective	Ref.
Therapeutic efficacy in ARDS	Weaker effect; pulmonary edema persists, limited recovery	Superior effect; reduced pulmonary edema and improved systemic recovery	Therapeutic benefit depends on endothelial stabilization and inflammation resolution, both more effectively addressed by CD146+ cells	[1,5]
Immunomodulation	Weak Th1/Th17 suppression, limited Treg induction	Strong Th1/Th17 inhibition and marked Treg expansion	CD146+ MSCs exert deeper immune rebalancing, potentially extending use to autoimmune conditions	[5,9]
Paracrine signaling and secretory activity	Low production of HGF, PGE2, VEGF, Ang-1	High production of HGF, PGE2, VEGF, Ang-1	CD146 reflects a “high-secretory phenotype”, suggesting their EVs/secretome are also more potent	[5,6]
Endothelial barrier repair	Low VE-cadherin and ZO-1 expression	High VE-cadherin and ZO-1 expression	Barrier integrity is central in ARDS pathophysiology; CD146+ cells directly fortify endothelial junctions	[5]
Angiogenic potential	Poor tube formation	Strong tube formation	Vascular repair and perfusion recovery are essential for lung healing	[5,8]
Key signaling pathway	Weak NF-κB/COX-2 activation	Strong NF-κB/COX-2 activation	These pathways drive pro-regenerative factor release and may be pharmacologically targetable	[5,7]
Effect of culture conditions	Low CD146+ ratio	High CD146+ ratio (in YF medium)	Standardization of manufacturing conditions influences potency by altering CD146+ subpopulation frequency	[5,16,17]

Data are summarized from Zhang et al[5] and the related literature. MSCs: Mesenchymal stromal cells; ARDS: Acute respiratory distress syndrome; Th1: Type 1 helper T; Th17: Type 17 helper T; Treg: Regulatory T; HGF: Hepatocyte growth factor; PGE2: Prostaglandin E2; VEGF: Vascular endothelial growth factor; Ang-1: Angiopoietin-1; EVs: Extracellular vesicles; VE-cadherin: Vascular endothelial cadherin; ZO-1: Zonula occludens-1; NF-κB: Nuclear factor kappa-B; COX-2: Cyclooxygenase-2.

Activation of the NF-κB pathway is directly related to increased secretion of key therapeutic factors. When inhibited by caffeic acid phenethyl ester, the secretion of HGF, PGE2, Ang-1, and VEGF by CD146+ MSCs was partially reversed. Furthermore, when NF-κB (p65) was directly suppressed in CD146+ MSCs, a significant decrease in HGF, PGE2, and VEGF secretion was observed, confirming the regulatory role of this pathway[5]. This paracrine profile exhibits a functional signature that concurrently facilitates angiogenesis, maintains endothelial barrier integrity, and promotes the resolution of inflammation[7,8]. It has been demonstrated that CD146+ subpopulations possess enhanced capabilities for Matrigel tube formation and angiogenic gene expression (Figure 3C in the original article)[5]. Additionally, the immunomodulatory effects of CD146+ MSCs, particularly the suppression of Th17 and augmentation of Treg cells, have been substantiated in independent models (Figure 3D in the original article)[5,9]. Ultimately, CD146+ cells significantly expedited lung barrier repair and resolution of inflammation in an ARDS model (Figure 4 in the original article)[5]. Nevertheless, the molecular mechanism of the “upstream” cascade from the CD146 surface to NF-κB activation is not completely understood. Addressing this research gap has the potential to reveal novel targets for pharmacological pre-conditioning.

RESTORATION OF VASCULAR ENDOTHELIAL CADHERIN AND ZONULA OCCLUDENS-1, ALONG WITH THE REPAIR OF BARRIER INTEGRITY AND PERMEABILITY

The integrity of the endothelial barrier is essential for maintaining the fluid balance and gas exchange capacity in the lungs. The intercellular junctions that constitute this barrier are regulated by adherens junctions and tight-junction complexes. Vascular endothelial cadherin (VE-cadherin) serves as the primary structural component of adherens junctions, facilitating stable contact between endothelial cells. Zonula occludens-1 (ZO-1), on the other hand, associates with tight junction proteins, integrates with the cytoskeleton, and regulates intercellular permeability[10-13]. In the pathophysiology of ARDS, disruption of these junctions results in increased microvascular permeability and onset of pulmonary edema. Consequently, VE-cadherin and ZO-1 are frequently used as biomarkers for endothelial barrier function. The study conducted by Zhang et al[5] demonstrated that the expression of VE-cadherin and ZO-1 was significantly elevated in ARDS mice treated with CD146+ MSCs compared to those treated with CD146- cells. This finding indicates that the therapeutic effects of CD146+ MSCs extend beyond the suppression of inflammation and directly contribute to the repair and maintenance of the endothelial barrier. This effect is clinically significant in conditions characterized by vascular leakage, such as ARDS[5,14].

PRODUCTION REALITY: “THE PROCESS IS THE PRODUCT”

Phenotype-focused production

It is well established that varying culture conditions significantly influence the phenotype and function of MSCs. Factors such as oxygen tension, matrix/substrate, and inflammatory stimuli can modify the paracrine output and surface marker patterns of MSCs[2,15]. There is a significant need to transition MSC production towards phenotype-based protocols that account for not only cell numbers but also “quality markers” such as CD146[16]. Additionally, phenotype-based production that preserves or enriches the CD146+ fraction and employs standardized quality metrics [e.g., %CD146+, extracellular vesicle (EV)/secretome profile, and functional potency assays] is essential for ensuring clinical consistency[16,17].

From single marker to panel approach: Beyond CD146

CD146 is recognised as a robust perivascular marker, however, other markers such as CD271 low-affinity nerve growth factor receptor, stromal precursor antigen-1, CD106 vascular cell adhesion molecule-1, and stage-specific embryonic antigen-4, are instrumental in identifying functional subpopulations associated with progenitor enrichment, immunomodulation and pluripotency-like phenotypes respectively[4,18]. For this reason, in complex pathologies such as ARDS, it may be prudent to base the most effective product not on a single marker, but rather on phenotype panels such as CD146+/CD271+. Evaluating these potent markers, both individually and in combination with various panels, will illuminate their individual sufficiency. And therefore, the necessity of employing these combinations should be critically assessed.

DISEASE-SPECIFIC CELL IDENTITY AND SOURCES

CD146 has been recognized as a significant marker for ARDS; however, markers such as CD106, stromal precursor antigen-1, and CD271 may be more appropriate for other diseases[18]. Furthermore, the source of the cells is critical. Deriving MSCs from various sources, such as bone marrow, adipose tissue, and umbilical cord, results in systematic differences in properties such as homing, proliferation, and immunomodulation[2]. Notably, umbilical cord-derived MSCs subpopulations have been shown to exhibit strong anti-inflammatory effects (increased Treg induction, enhanced macrophage phagocytic activity, and increased VEGF secretion)[19]. While bone marrow-derived CD146+ MSCs demonstrate superior migration and homing capacity, adipose tissue-derived MSCs tend to exhibit enhanced proliferation and angiogenic activity[18,19]. However, rodent lipopolysaccharide-ARDS models do not fully capture the clinical heterogeneity of ARDS[1]. Therefore, phenotype-focused assessments should be conducted in ARDS models across diverse aetiologies (e.g., pneumonia, sepsis, and trauma), particularly given that Zhang et al[5] demonstrated that the therapeutic effects of CD146+ MSCs are largely mediated by paracrine factors (Figure 3B in the original article). Collectively, these findings indicated that strategies involving MSCs should be developed with a dual focus on phenotype-driven cell selection and exploring next-generation cell-free therapeutic models.

LIMITATIONS AND OUTLOOK

Despite these promising trends, certain limitations must be considered. First, Zhang et al[5] and much of the existing supporting literature rely on preclinical models that capture only a portion of the clinical heterogeneity of ARDS. Second, while the enrichment of CD146+ subpopulations is an impressive strategy, isolating MSC subgroups and standardizing functional potential testing continue to pose technical challenges across manufacturing platforms. Addressing these limitations through standardized potency assays, scalable production methods, and integrated preclinical-clinical validation processes are essential for advancing the vision of developing precision cell therapy. Exploring next-generation cell-free approaches may also offer complementary solutions to mitigate some of the current limitations.

FUTURE PERSPECTIVES

The progression of coronavirus disease 2019 (COVID-19) to ARDS, which frequently manifests with diverse clinical and physiological phenotypes[20], has underscored the global imperative for innovative treatments aimed at mitigating severe lung injury. Clinical data from hospitalized patients show that viral load, inflammatory cytokine levels, and biochemical markers such as D-dimer and tissue plasminogen activator are closely associated with the severity and poor prognosis of COVID-19 related ARDS[21,22]. Global analyses on the incidence of ARDS in COVID-19 patients clearly demonstrate the unmet need for regenerative and immunomodulatory strategies to restore alveolar-capillary barrier integrity and resolve the hyperinflammatory state[21-23]. In this context, MSC-based and cell-free (including EV) strategies have emerged as promising therapeutic approaches for viral and inflammatory lung injuries. Notably, the findings reported by Zhang et al[5] aligned with this emerging perspective, emphasizing the importance of targeted phenotype-focused MSC approaches for ARDS of varying etiologies.

EVs present a particularly promising avenue, offering the potential to address significant translational challenges associated with live-cell therapies. In this clinical framework, EVs derived from MSCs are emerging as a next-generation cell-free therapeutic strategy and are increasingly recognized as a potentially transformative avenue for treating ARDS. EVs have the potential to enhance and refine the therapeutic principles established by Zhang et al[5], offering novel opportunities to mitigate tissue damage in both infectious and noninfectious cases of ARDS.

A major limitation of MSC-based therapies is cellular heterogeneity resulting from donor variability, tissue sources, and culture conditions, which can lead to inconsistencies in clinical outcomes and render treatment efficacy unpredictable[1,2]. In contrast, EVs obtained from a specific subpopulation such as CD146+ MSCs, may provide more standardized and reproducible therapeutic products. Given that the therapeutic effects of MSCs are largely mediated through paracrine factors (for example, HGF, VEGF, and PGE2), EVs can be considered concentrated carriers of these biological factors. Dutra Silva et al[14] in 2021 demonstrated that MSC-derived EVs alone could restore mitochondrial function and endothelial barrier integrity. This finding supports the potential of cell-free therapeutic approaches as significant alternatives in the future.

Considering the potent secretory and immunomodulatory profiles of CD146+ MSCs, it is plausible that EVs derived from these cells may exhibit similar or even greater therapeutic efficacy[4]. Therefore, future studies should investigate whether EVs derived from CD146+ MSCs are enriched in COX-2/NF-κB-mediated regulators. Beyond their biological activity, EVs offer distinct translational advantages over live cell therapies: they present a lower risk of ectopic differentiation or immune activation, better storage stability and high scalability for clinical production[24-29].

However, current evidence on EVs is predominantly based on preclinical models. Key translational aspects, including dose standardization, pharmacokinetic profiles, and long-term safety require detailed exploration in future translational studies. Thus, although EVs represent a promising cell-free extension of MSC-based therapies, their clinical applicability depends on rigorous validation studies at both mechanistic and regulatory levels.

CONCLUSION

The research conducted by Zhang et al[5] advocates for a shift in MSC-based therapies from the traditional focus on “cell count” to a precision based approach centered on the principle of “right phenotype-right patient-right indication”. When integrated with existing mechanistic insights, CD146+ MSCs have emerged as the most promising therapeutic subpopulation for ARDS treatment (Table 1). However, the next phase of precision cell therapy may extend beyond the use of live cells. By systematically characterizing EVs and secretomes derived from CD146+ subpopulations, it is possible to develop standardized, scalable, and cell-free therapeutic products. Concurrently, the employment of advanced microphysiological 3D models, such as “lung-on-a-chip”[30], is critical for validating the next-generation approaches under physiological conditions.

ACKNOWLEDGEMENTS

The author acknowledges Prof. Dr. Ayla Eker Sarıboyacı (Eskişehir Osmangazi University, ESTEM) and Prof. Dr. Varol Şahintürk (Department of Histology and Embryology, Eskişehir Osmangazi University) for their mentorship in stem cell biology and related to molecular approaches, which helped shape the author’s scientific perspective.