In the evolving landscape of regenerative medicine, mesenchymal stem cells (MSCs) have emerged as a promising beacon of hope for treating a spectrum of lung diseases. Their unique capability to modulate the immune system, coupled with regenerative potential, has drawn intense scientific focus. Nonetheless, while the therapeutic applications of MSCs for pulmonary disorders harbor immense potential, the journey from bench to bedside remains fraught with complex challenges that demand rigorous investigation.
The clinical spotlight on MSCs has predominantly illuminated their utility in addressing acute respiratory conditions, notably the severe manifestations of coronavirus disease 2019 (COVID-19) and acute respiratory distress syndrome (ARDS). Current therapeutic trials predominantly reside within early-stage clinical phases, primarily phases I and II, where safety and preliminary efficacy are explored. However, the progression to expansive phase III trials, essential for broader clinical validation and regulatory approval, remains a milestone yet to be attained. This gap underscores the critical need for refining the therapeutic protocols and overcoming the inherent obstacles within MSC transplantation.
A fundamental barrier to the seamless clinical application of MSCs lies in their intrinsic heterogeneity. These cells, isolated from diverse tissue sources – including bone marrow, umbilical cord, and amniotic membrane – exhibit notable variability. Although they uniformly express common surface markers such as CD29, CD44, CD73, CD90, and CD105, their paracrine activity, immunomodulatory potency, and regenerative efficacy differ substantially depending on their origin. Intriguingly, even MSCs derived from identical tissue types but different donors reveal variability, influenced by factors that range from donor age to the subtle nuances of cell culture environments.
Donor age particularly emerges as a crucial determinant that inversely correlates with MSC functionality. With increasing age, MSCs demonstrate a marked decline in their differentiation potential, homing capacity, ability to regulate immune responses, and resilience against oxidative stress. This age-associated attrition significantly complicates the standardization of MSC preparations, especially when the therapeutic goal demands a robust and consistent cell population. Beyond donor-related variables, cell culture conditions impose another layer of complexity, as parameters such as cell seeding density, growth medium composition, and oxygen tension dynamically alter gene expression profiles, epigenetic landscapes, and phenotypic traits of MSCs.
Moreover, the process of in vitro cell expansion, indispensable for generating therapeutic quantities, introduces further unpredictability. MSCs are typically propagated through several passages, with current clinical protocols favoring passages three to seven to balance expansion and potency. However, progressive passaging inevitably leads to phenotypic drift, altering the cells’ biological characteristics and potentially diminishing their therapeutic value. The lack of a universally accepted MSC subpopulation definition complicates quality control, necessitating multifaceted identification strategies employing positive markers such as CD90 and CD105, alongside negative selection against hematopoietic markers like CD34 and CD45.
Safety concerns stand as a paramount challenge in the clinical translation of MSC therapies. Immunocompatibility issues, although partly mitigated by the cells’ immunomodulatory nature, still present risks, especially in allogeneic transplant settings. Perhaps more alarming is the specter of tumorigenicity attributed to MSCs’ self-renewing capabilities. Accumulating evidence paints a complex picture: within tumor microenvironments, MSCs can contribute to pathology by differentiating into stromal components that support tumor growth, suppressing anti-tumor immune responses, enhancing angiogenesis, promoting tumor cell survival, and facilitating metastatic dissemination. These oncogenic potentials necessitate meticulous scrutiny when designing MSC-based interventions.
Further complicating the therapeutic landscape is the physical fate of MSCs post-administration. The predominant intravenous delivery route frequently results in significant cell entrapment within pulmonary microvasculature. This phenomenon not only limits the number of MSCs reaching diseased tissue sites but also introduces the risk of microvascular occlusions and thrombotic events. Reports of adverse events, such as pulmonary embolisms observed in certain clinical studies employing Wharton’s jelly-derived MSCs, underscore the urgency for safer delivery methodologies or alternative therapeutics.
In addressing the viability and function of transplanted MSCs, it is noteworthy that apoptosis and autophagy manifest swiftly following systemic administration. This rapid attrition curtails therapeutic efficacy, compelling researchers to explore preconditioning or priming techniques. Preconditioning strategies encompass a spectrum of approaches, including genetic modifications, hypoxic culture conditions, exposure to inflammatory mediators, supplementation with bioactive compounds, three-dimensional culture systems, co-culture with disease-specific cell types, and addition of patient-derived serum. These interventions aim to enhance MSC survival, augment therapeutic payloads, and tailor immunomodulatory functions in vivo.
Amid these complexities, MSC-derived extracellular vesicles (MSC-EVs) have surfaced as an alluring alternative or adjunct to cell-based therapies. Bearing a high degree of biocompatibility and lacking the self-replicating risks linked to living cells, MSC-EVs circumvent many safety hurdles. Their nano-scale size facilitates excellent biobarrier penetration and diminishes the possibility of vascular embolism. Moreover, MSC-EVs exhibit remarkable stability and ease of storage compared to living cells, heralding practical advantages for clinical application.
Yet, the clinical promise of MSC-EVs is counterbalanced by significant technical obstacles. The absence of scalable, standardized production protocols hampers the consistency and quantity of EVs required for therapeutic use. There remains a conspicuous lack of consensus on optimal isolation, characterization, and handling techniques, complicating regulatory approval processes. Furthermore, critical questions concerning the appropriate therapeutic dosing and ideal administration routes – whether systemic or localized – remain open, mirroring uncertainties encountered in MSC therapies themselves.
The encapsulated understanding from current research illustrates a nuanced interplay between the biological potential of MSCs and the multifaceted challenges impeding their translation into widely accessible lung disease treatments. Researchers worldwide continue to dissect the molecular underpinnings of MSC function and seek innovative methodologies to standardize their therapeutic attributes. Emphasis is also placed on elucidating the mechanisms governing MSC interactions within damaged pulmonary microenvironments to optimize their reparative efficacy.
Future directions in this arena likely involve integrative technologies combining MSC biology with cutting-edge bioengineering, genetic editing, and precision medicine frameworks. These approaches promise personalized, efficacious, and safer stem cell-based therapies customized for individual patient profiles and disease etiologies. Moreover, as breakthroughs in extracellular vesicle research accelerate, the translation of MSC-EV-based regimens could revolutionize treatment paradigms, offering cell-free alternatives characterized by enhanced safety, stability, and therapeutic nimbleness.
While the clinical horizon for MSC applications in lung disease is undeniably bright, it is equally marked by pressing challenges that necessitate collaborative, multidisciplinary research efforts. Only through meticulous refinement of cell sourcing, culture protocols, safety evaluations, dosing regimens, and delivery strategies can MSCs or their derivatives fulfill their transformative potential in combating devastating pulmonary illnesses.
Subject of Research: Mesenchymal stem cells (MSCs) and their application in treating lung diseases, with a focus on immunomodulatory actions and therapeutic challenges.
Article Title: Mesenchymal stem cells for lung diseases: focus on immunomodulatory action.
Article References:
Feng, Y., Lu, J., Jiang, J. et al. Mesenchymal stem cells for lung diseases: focus on immunomodulatory action. Cell Death Discov. 11, 52 (2025). https://doi.org/10.1038/s41420-025-02303-4
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