Chronic wounds are defined as skin or soft tissue injuries that fail to progress through the normal stages of healing within a typical timeframe, generally persisting for more than 3 months (Li and Zheng, 2024). Examples of chronic wounds include diabetic foot ulcers (DFUs), pressure ulcers (PUs), and venous leg ulcers (VLUs) as well as iatrogenic lesions such as radiation-induced ulcers that develop after radiotherapy These wounds exhibit a high incidence and recurrence rate and are often refractory to treatment (Li et al., 2023; Liu et al., 2024; Jones et al., 2018). The pathophysiology of chronic wounds is complex and multifactorial, involving factors such as chronic inflammation, hypoxia, infection, vascular insufficiency and cellular dysfunction. Although chronic wounds share several core pathological features, different etiological subtypes—such as neuropathic DFUs, ischemia- and pressure-driven ulcers and radiation- induced ulcers characterized by microvascular rarefaction and fibrosis—arise from distinct combinations of these mechanisms. These elements are critical to the healing process, and impaired healing results in prolonged suffering, significantly diminishing the patient’s quality of life (Abbott et al., 2019; Li et al., 2021; Schilrreff and Alexiev, 2022).

Chronic wounds represent a substantial global healthcare burden. Epidemiological studies estimate that 19%–34% of diabetic patients will develop DFUs, with approximately 15% experiencing at least one ulceration during their disease course (Rastogi et al., 2020). The prevalence of PUs ranges from 2.5% to 15% among hospitalized patients, and up to 30% in long-term care facilities (Tomova-Simitchieva et al., 2019). VLUs affect 1%–2% of the general population, with a higher prevalence among the elderly (Probst et al., 2023). As survival rates for cancer patients continue to improve, the prevalence of chronic wounds caused by radiation therapy (burns) will grow along with this increase in cancer patient survivors. These will create an additional burden of care for patients previously treated with radiation therapy as the incidence of chronic wounds from radiation continues to grow. The economic burden of chronic wounds is significant, with the annual direct cost of DFU management in the United States estimated at USD 9.7 billion, and an additional USD 9 billion spent on PU management (Sa et al., 2024; Kuikko et al., 2024). Beyond the financial costs, patients endure severe pain, functional impairment, infection risk, and psychosocial distress, with advanced DFUs leading to a high risk of lower-limb amputation—only 50% of which result in survival beyond 5 years (Schreml and Berneburg, 2017; Hicks et al., 2019).

Standard treatments, including negative pressure wound therapy (NPWT), growth factor therapy, and surgery, offer temporary relief at best (de Oliveira et al., 2018). However, they fail to address the underlying pathological imbalances within the wound microenvironment, and these interventions do not effectively reverse chronic inflammation, promote angiogenesis, or restore cellular function. This limitation is found in all types of chronic wounds, but is especially noticeable in the formation of iatrogenic lesions, including those caused by radiotherapy-induced ulceration, which in many cases, severely limit the ability of reconstructive techniques to restore tissues to normal function due to the presence of extensive microvascular damage and extensive fibrosis. Consequently, there is a pressing need to develop new therapies that focus on healing the wound rather than merely managing symptoms (Oe et al., 2022). The limitations of current treatments highlight the need for more effective approaches, such as:

Negative pressure wound therapy (NPWT): Improves local perfusion and granulation tissue formation but does not resolve chronic inflammation or cellular senescence (Takagi et al., 2020; Norman et al., 2022).

These differences between acute and chronic wound healing are summarized in Figure 1, highlighting the pathological barriers that MSC-based therapies are uniquely positioned to overcome. Given these challenges, MSC-based therapies, which address multiple aspects of the wound-healing process, are best conceptualized as adjuncts or biological intensifiers of conventional treatments rather than stand-alone alternatives. When added on top of standard wound care—including debridement, infection control, off- loading, revascularization and advanced dressings—MSCs may exert complementary and even synergistic effects on the chronic wound microenvironment. strategies and are likely to be used in combination with, rather than as a replacement for, conventional treatments. The primary objectives in chronic wound management are to accelerate tissue repair, control infection, and enhance quality of life (Savelieff et al., 2025). Nevertheless, conventional therapies remain insufficient because they fail to correct the pathological microenvironment.

Mesenchymal stem cells (MSCs) are multipotent adult progenitor cells that were first described in bone marrow and have since been identified in adipose tissue, umbilical cord, placenta and many other sources (Dipalma et al., 2025; Daltro et al., 2020; AJ, 1968). The three main properties of MSCs are multi-lineage differentiation, immunomodulation, and paracrine signaling, which define their therapeutic warrant in regenerative medicine (Kobolak et al., 2016; Lelek and Zuba-Surma, 2020).

Chronic wounds such as diabetic foot ulcers, pressure ulcers, and venous leg ulcers have specific characteristics of chronic inflammation, ineffective angiogenesis, and aberrant extracellular matrix remodeling, which serves as obstacles to healing (Kouroupis et al., 2023). The employment of MSCs provides a counter to these chronic wound characteristics. MSCs mitigate chronic inflammation by secreting anti-inflammatory cytokines (i.e., IL-10, TGF-β) and by modulating immune cell populations (Azevedo et al., 2020; Darlan et al., 2021; Aulia et al., 2024). MSCs will further mediate chronic wound repair through paracrine secretion of growth factors, such as VEGF, HGF, and bFGF, which promote angiogenesis in addition to cell proliferation and survival to improve the formation and re-epithelialization of granulation tissue. Although MSCs can differentiate into fibroblasts, endothelial cells, and keratinocytes, this differentiation process is controversial and is not definitively proven. Current models of chronic wound healing emphasize primarily the paracrine and immunomodulatory properties of MSCs as the mechanisms responsible for effecting healing (Cao et al., 2017; Legrand and Martino, 2022; Fernandes et al., 2020; Garikipati et al., 2018; Akasaka, 2022; Kieper et al., 2010; Fang et al., 2020).

At the molecular level, MSCs act mainly via paracrine signalling and extracellular vesicles (EVs) to recalibrate chronic wounds: they resolve inflammation by downregulating NF-κB/NLRP3 and skew macrophages towards M2 via IL-10/TGF-β signalling (Al-Shaibani et al., 2024); promote angiogenesis through the HIF-1α → VEGF axis and pro-angiogenic miRNAs (e.g., miR-126/miR-210) (Pea and Martin, 2024); accelerate re-epithelialisation via EGFR/ERK and Wnt/β-catenin cues (Mamun et al., 2024); and normalise ECM turnover via TGF-β/Smad with a balanced MMP/TIMP programme. These pathway-level effects provide the mechanistic basis for the improvements observed in preclinical and early clinical studies.

Preclinical studies demonstrate that MSCs restore wound homeostasis and facilitate closure, and early phase clinical trials are now confirming their potential as a therapeutic modality (Kouroupis et al., 2023). Regardless, substantial translational barriers exist, including source heterogeneity, variability from donor to donor with respect to immunomodulatory capacity, variability in manufacturing processes, variability in delivery approaches, and limited long-term safety data (Volarevic et al., 2018; Maldonado et al., 2023; Chen and Liu, 2016). If these translational barriers can be overcome, with particular reference to potency assays that can be standardized, along with rational clinical guidelines, MSCs can take their place as reliable, reproducible and clinically useful acute or chronic wound therapies.

This review aims to comprehend worldwide studies related to the use of mesenchymal stem cells (MSCs) to manage chronic wounds, focusing on three principal domains: (i) the biological effects of MSCs related to differentiation, immune modulation, and paracrine activity; (ii) clinical studies of MSCs from preclinical and clinical data; and (iii) the current obstacles to the translational uptake of MSC therapies into clinical practice. This review seeks to summarize the research evidence to date that relates MSC activity to tissue repair, illuminate key considerations for future research, and review important gaps in the evidence needed to advance MSC therapies into a clinical setting. The impact of MSC therapies on patients clinically and societally is significant, potentially improving the quality of life for patients with acute or chronic wounds, while simultaneously reducing the economic burden chronic wound care places on the healthcare system, should MSC therapy prove effective. Thus, even should MSC therapies be successful and clinical, substantial obstacles still remain to enable the full potential of this therapy including efficacy due to sample source heterogeneity, safety concerns, and developing treatment protocols and standardized processes. Ultimately, successful MSC therapies in a clinical setting could be a game-changer for managing chronic wounds and has the potential to broaden to other therapeutic areas in regenerative medicine (Figure 2).

Mesenchymal stem cells (MSCs) promote wound healing primarily by secreting bioactive molecules, particularly key growth factors involved in angiogenesis, cellular proliferation, and extracellular matrix (ECM) remodeling (Harrell et al., 2019b; Legrand and Martino, 2022). In addition to soluble factors, extracellular vesicles, including exosomes, also act as important carriers of these paracrine signals and will be discussed in more detail in Section 2.4. Vascular endothelial growth factor (VEGF) and fibroblast growth factors (FGFs) are key regulators of angiogenesis by promoting endothelial cellular proliferation and migration, as well as lumen formation via phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases (MAPK) signaling pathways (Wang et al., 2019; Kasowanjete et al., 2024). Beyond driving the core processes of angiogenesis, VEGF increases vascular permeability, thereby facilitating the recruitment of endothelial progenitor cells to the injury site, whereas FGFs upregulate the production of matrix metalloproteinases (MMPs), which are essential for ECM remodeling and for the ingrowth of new blood vessels (Sung et al., 2021). Cytokines derived from MSCs, such as interleukin-6 (IL-6) and IL-8, aid the angiogenic process by promoting the expression of VEGF and FGF which, in turn, amplifies the overall healing cascade (Harrell et al., 2019b; Fernandes et al., 2020). In addition to angiogenesis, MSCs also secrete epidermal growth factor (EGF) and keratinocyte growth factor (KGF) which stimulate keratinocyte proliferation, migration, and differentiation via the EGF receptor (EGFR) and FGF receptor 2b (FGFR2b) respectively (Zhang et al., 2023). Transforming growth factor-β (TGF-β) derived from MSCs promotes fibroblast differentiation and drives the production of collagen and other ECM components that provide structural support during epithelial barrier repair (Akasaka, 2022). Collectively, these paracrine signaling mechanisms create a localized environment that supports angiogenesis and simultaneously sustains dynamic epithelial repair. Some of these mediators also contribute to immunomodulation, which is further elaborated in Section 2.2. While the paracrine effects of MSCs are clearly beneficial, recent studies suggest that successful wound repair relies on the coordinated activation of multiple signaling pathways rather than isolated mechanisms (Zhang et al., 2024). Moreover, this new potential has led researchers to explore the genetic modification of MSCs and to enhance bioactive molecules in exosomes. However, we are still faced with many challenges, especially the dynamics, stability, reproducibility, and therapeutic efficiency of these bioactive molecules when considering the clinical setting (Yang Q. et al., 2022). We still have to address many of the issues faced in current clinical practice with not only the standardization of MSC-based therapy but also with the potential mechanisms of delivery for consistent control of delivering bioactive molecules (Maldonado et al., 2023). Therefore, the establishment of standardization and controlled procedural mechanism will be paramount for the clinical success and usefulness of cell-based (MSCs) therapy in clinical care.

As outlined in Section 2.1, the broad repertoire of soluble factors and extracellular vesicles released by MSCs forms the basis of their immunomodulatory capacity. By acting on both innate and adaptive immune cells, these paracrine mediators play a key role in dampening chronic inflammation that can arise during impaired tissue repair. MSCs secrete a wide variety of compounds that modulate the immune response, including prostaglandins, interleukins, and transforming growth factor-beta. These together establish an anti-inflammatory state and assist in shifting macrophage populations from pro-inflammatory M1 to reparative M2 macrophages (Azevedo et al., 2020; Ong and Dilley, 2018). In addition, MSC- derived exosomes contain microRNAs (miRNAs), such as miR-21 and miR-146a, that exert pro-reparative effects on macrophage polarization by enhancing macrophage function through metabolic reprogramming (Chen et al., 2022). In terms of adaptive immunity, mesenchymal stem cells (MSCs) enhance both generation and expansion through the production of IL-10 and TGF-β to produce Tregs while decreasing the number of activated effector T cells (such as called Teff) and balancing out subtypes of Th1/Th2 with Th17/Treg (Lee et al., 2016). Through their exosomes, MSCs inhibit the activation of the NF-κB signalling cascade and other pro-inflammatory pathways in Tregs during their maturation process, thus creating an immunosuppressive environment (Chen et al., 2024). The effects of the differentiation of Tregs involve an interaction between M2-macrophages and Tregs, with M2-macrophages secreting IL-10 and TGF-β to promote the differentiation of Tregs, creating a further enhancement of the anti-inflammatory environment that they produce (Ivanovski et al., 2024). Due to the combined paracrine-mediated immunomodulatory effects of MSCs, there has been significant interest in utilizing MSC therapy for chronic wounds as well as other immunological diseases. Despite the increased interest surrounding the potential use of MSCs for regenerative medicine, there remain numerous challenges associated with MSC therapies that impede their transition from bench to bedside. These challenges include the variability in MSC characteristics and immunosuppressive activities based upon tissue source, the potential risks associated with excessive/non- specific immunosuppression, and the lack of standardized assays to assess MSC potency. In order to achieve the maximum potential level of safety and effectiveness of MSC therapies, addressing these issues is critical (Table 1).

While it is likely that the predominant mechanisms of mesenchymal stem cells (MSCs)-mediated wound repair is through paracrine signaling and immunomodulation, it is possible that MSCs may contribute through their own differentiation into tissue specific lineages. In chronic wound settings, MSCs have demonstrated transition into fibroblasts, enhancing extracellular matrix (ECM) production and collagen deposition, with increased wound contraction (Kieper et al., 2010). In some cases, MSCs have demonstrated keratinocyte-like phenotypes, contributing to epidermal regeneration and re-epithelialization (Yoo et al., 2025). Regulation of lineage transitions seems to occur via some combination of growth factors and cytokines and their interactions with the ECM, resulting in local organization of the wound microenvironment- to varying degrees (Xu et al., 2024). While research has shown that direct differentiation is possible, the clinical relevance is questioned. Evidence suggests that while the frequency and stability of lineage commitment is important, it is dwarfed by the strong effects of direct paracrine signaling (Casado-Daz et al., 2020). Moreover, variability amongst donor cell type, culture conditions and local wound environments all remained unpredictable and reproducible (Chen et al., 2024). Therefore, while differentiation may offer structural support for repair, caution must be exercised in the interpretation of evidence to support a meaningful contribution. Future studies of MSCs should consider studies optimizing differentiation protocols, improving the microenvironmental cues supporting lineage specificity, and developing reliable in vivo tracking of MSC-derived cells. This will ultimately help decide if differentiation should be considered a clinically relevant mechanism, or merely a potential secondary source of benefit in addition to paracrine signaling and immunomodulatory functions (Volarevic et al., 2018).

As an integral component of the MSC secretome described above, exosomes produced by mesenchymal stem cells (MSC-Exos) have emerged as important contributors to paracrine signaling. They serve as nanoscale transport vehicles that deliver proteins, lipids and nucleic acids to target cells, thereby modulating angiogenesis, innate immune responses and epithelialization. MSC-exosomes are vesicles produced by mesenchymal stem cells (MSCs) that act as transporters of proteins, lipids and nucleic acids. They play a role in paracrine signaling between cells within tissues or organs. They contribute to the process of angiogenesis, by up-regulating vascular endothelial growth factor (VEGF) and activating the PI3K/AKT signaling cascade, and modulating the innate immune response and epithelialization through their miRNA content (Azevedo et al., 2020; Kasowanjete et al., 2024). Several different types of exosomal microRNA (miRNA) exist, which are involved in regulating various cellular processes, including pro-angiogenesis (upregulation of VEGF) through the PI3K - AKT signaling pathway and promoting the proliferation and migration of endothelial cells through the ERK- MAPK pathway via exosomal protein transfer to endothelial cells. There exists a diverse miRNA content among exosomes that have an immunomodulatory activity, including miR-146a and miR-21, which both downregulate NF-κB signaling and induce M2 macrophage polarization while at the same time reducing the production of pro-inflammatory cytokines (Darlan et al., 2021). Exosomes contain epidermal growth factor (EGF), which promotes keratinocyte growth and stabilization of the epithelial barrier and is thought to mediate these effects via the Wnt/β -catenin signaling pathway (Wang et al., 2014). In combination, these angiogenic, immunomodulatory and pro-epithelial effects enable MSC-Exos to orchestrate a complex signaling network that, in many respects, recapitulates the therapeutic actions of whole-cell MSC therapy. This has positioned MSC-Exos as a promising cell-free approach for the treatment of chronic wounds (Kouroupis et al., 2023). In addition, MSC-Exos may reduce several risks associated with live cell transplantation, including uncontrolled cell proliferation and tumorigenicity. While MSC-Exos have many advantages, there are still many challenges to be addressed before they can be routinely used in clinical practice. Examples of these challenges are the variations in exosome components that can be caused by how the MSC was obtained, the environment where it was cultured, and how the exosomes were separated from the cells, all of which will affect the consistency of their effectiveness for therapeutic use (Mendicino et al., 2014). While large-volume production of exosome products represents a logistical challenge, their bioactivity may be adversely affected by prolonged periods of storage and transportation (Song et al., 2018). In addition, the absence of a sufficient number of standardized potency and dose-response evaluations makes it very difficult to determine the appropriate dose and therefore establish a suitable regulatory framework (Deng et al., 2023).

To successfully navigate and conquer these obstacles, it is necessary to develop and promote standardized methodologies/protocols for isolating exosomes from MSCs so that the exosomal content can be more accurately characterized and agreed upon between regulatory authorities, researchers, and clinicians alike (Chen and Liu, 2016). Once these issues have been resolved, MSC-derived exosomes (MSC-Exos) will be able to proceed from the laboratory to clinic-based care with appropriate dosage forms based on the therapeutic efficacy of MSC-Exos when produced from various sources of MSCs and using different manufacturing techniques.

Chronic wounds persist in a challenging microenvironment defined by high inflammation, ongoing infection, and combined hypoperfusion/hypoxia and oxidative stress (Zhu et al., 2023; Wang C. et al., 2024). These factors determine the fate of mesenchymal stromal/stem cells (MSCs) for survival, homing, and persistently could affect therapeutic outcome and safety (Zhu et al., 2023; Gao et al., 2024). Evidence suggests that MSC fates in chronic wounds are incumbent upon:

Programmed cell death induced by the accumulation of inflammatory cytokines or reactive oxygen species followed by clearance by the immune system which shortens the time MSCs will remain in situ and the duration of therapeutic window (Gao et al., 2024; Wang R. et al., 2025);

An overview of representative stem cell -based clinical trials and their applications in chronic wound healing is summarized in Table 3. The efficacy of mesenchymal stromal cell (MSC) therapy has progressed through phase I/II studies that report acceptable safety, tolerability, and preliminary benefit for chronic wounds, including diabetic foot ulcers (DFUs), venous leg ulcers (VLUs), and pressure injuries (PIs) (Kishta et al., 2025). The studies highlighted promising findings, but importantly, limitations in the small number of patients, limited time of follow-up, and randomness with which patients are treated, suggest more studies are required in order to implement MSC therapy and support additional use for chronic wounds (Mahmoudvand et al., 2023).

Diabetic Foot Ulcer (DFU): The evidence for the use of MSCs in DFU healing is growing. Wharton’s jelly- derived MSC exosomes were applied topically in a randomized double-blind trial and showed significant improvement in the healing rate, with complete epithelialization seen in a mean of 6 weeks (compared to 20 weeks for the control group) (Kishta et al., 2025). A pilot trial of umbilical cord MSCs, using both perilesional and intravenous administration, showed complete wound closure in a mean of 1.5 months in 80% of patients, with great long-term outcomes and minimal adverse events reported (Zhang et al., 2022). These prior studies are consistent with other studies that highlight the regenerative potential of MSCs for diabetic foot ulcers, suggesting that MSC therapy could reduce time-to-heal and prevent amputations (Sieko et al., 2024).

Venous Leg Ulcer (VLU): For refractory VLUs, autologous bone marrow MSCs were applied in a fibrin spray format and showed a healing rate 10 times higher than the control group, with no serious adverse events reported (Mahmoudvand et al., 2023). Additionally, a phase I/II randomized controlled trial (RCT) is currently underway assessing an allogeneic MSC-seeded biological dressing (BAMS), standardizing biologic off-the-shelf treatment for chronic VLUs. This reflects the increasing interest in cellular therapies for VLU patients (Costela-Ruiz et al., 2025).

Pressure Injuries (PI): Human clinical data for MSCs in PI are limited, but case reports suggest that MSCs (particularly from Wharton’s jelly) show potential for healing when combined with platelet-rich plasma (PRP). One report of a hospital-acquired pressure ulcer showed near-complete healing after 7 weeks of this product being applied, with no adverse events reported (Zhou et al., 2024). Ongoing translational studies utilizing MSC-loaded hydrogels and engineered patches could potentially improve local retention and survival of MSCs in pressure ulcers. However, robust RCTs will be needed to demonstrate efficacy (Barbon et al., 2025).

The important clinical takeaway from above is that mesenchymal stromal cell (MSC)–based interventions are typically used as adjuncts to optimized standard wound care rather than as a replacement for the standard treatment protocol. Most clinical protocols continue to have debridement, infection control, off-loading or compression, vascular optimization, and appropriate dressings as the foundational elements of the management of chronic wounds (Li and Zheng, 2024; Jones et al., 2018), with MSC products serving as biological modulators of the chronic wound environment. While standard management focuses primarily on biomechanical, infectious and ischaemic causative factors for chronic wounds (Sa et al., 2024), MSCs have immunomodulating, pro-angiogenic and pro-regenerative properties (Wu et al., 2024). Thus, MSC- based combination protocols are designed to provide a synergistic or complementary effect with standard management rather than to supplant it (Sukmana et al., 2023). In keeping with this adjunctive approach, emerging research is focused on combining MSCs with other enhanced therapies and biomaterials (Farag et al., 2024; Sukmana et al., 2023). For example, Khalil et al. found that the application of autologous adipose-derived MSCs in platelet-rich fibrin (PRF) with standard care improved rates of ulcer healing compared to PRF alone and raised no significant safety concerns (Khalil et al., 2021). Other reports have identified combinations of MSCs with platelet-rich plasma, fat grafts, dermal substitutes, biological dressings and hydrogel- or scaffold-based delivery systems for DFUs, VLUs and PIs (Xu et al., 2024; Fan et al., 2024). While most of the data available for these applications are preliminary and heterogeneous, collectively they point to the conclusion that MSCs should be considered more realistically as adjunctive and synergistic components of a multimodal approach to wound care rather than as replacements for current evidence-based standard management strategies (Spence and Gallicchio, 2022; Cames et al., 2020).

In summary, early studies show promise for efficacy in chronic wound healing with MSC therapy, and preliminary evidence is emerging. To further establish these findings, additional studies will need to be larger, multi-center RCTs utilizing standardized protocols and interoperable endpoints in order to evaluate the efficacy and safety of MSC therapy for DFU, VLU, and PI patients. Similar to previous commentary, care in determining the precise source of MSCs, route of delivery, and patient selection will ultimately be important to optimizing outcomes in chronic wound care (Zhu et al., 2023).

The emergence of mesenchymal stromal cells (MSCs) in addition to novel biomaterials and exosomes or exosome-like technologies readily increases their value in regenerative medicine. These techniques are compelling because they address two of the major shortcomings of MSC therapy, namely, poor cell viability in hostile wound niches and variability in therapeutic efficacy, by genetically providing 3D biomimetic microenvironments with controllable local drug delivery and enabling cell-free vesicles to maintain pro-regenerative signalling (Wang D. et al., 2025). However, considerable barriers to translating to clinical efficacies remain including optimization of mechanical properties of biomaterials, durability of in vivo biocompatibility and scalable production (Keshavarz et al., 2024).