Umbilical cord-derived mesenchymal stromal cells: Promising therapy for heart failure

Abstract

Heart failure (HF) is a complex syndrome characterized by the reduced capacity of the heart to adequately fill or eject blood. Currently, HF remains a leading cause of morbidity and mortality worldwide, imposing a substantial burden on global healthcare systems. Recent advancements have highlighted the therapeutic potential of mesenchymal stromal cells (MSCs) in managing HF. Notably, umbilical cord-derived MSCs (UC-MSCs) have demonstrated superior clinical potential compared to traditional bone marrow-derived MSCs; this is evident in their non-invasive collection process, higher proliferation efficacy, and lower immunogenicity and tumorigenicity, as substantiated by preclinical studies. Although the feasibility and safety of UC-MSCs have been tested in animal models, the application of UC-MSCs in HF treatment remains challenged by issues such as inaccurate targeted migration and low survival rates of UC-MSCs. Therefore, further research and clinical trials are imperative to advance the clinical application of UC-MSCs.

Key Words: Umbilical cord-derived mesenchymal stromal cells; Bone marrow-derived mesenchymal stromal cells; Cell therapy; Heart failure; Cardiovascular diseases

Core Tip: There has been increased emphasis on the efficacy and potential of umbilical cord-derived mesenchymal stromal cells (UC-MSCs) for reversing cardiac remodeling in heart failure. UC-MSCs exhibit low immunogenicity and tumorigenicity, with a painless, non-invasive collection process. Compared to bone marrow-derived mesenchymal stromal cells, UC-MSCs exhibit superior proliferation, migration, immunosuppressive effects, and paracrine activity. However, their efficacy largely depends on the primitive source and extraction/delivery methods. Therefore, optimizing extraction/delivery techniques and conducting rigorous clinical trials are essential for further clinical implementation of UC-MSCs in heart failure patients.

INTRODUCTION

Heart failure (HF) is a syndrome in which diverse etiologies precipitate aberrant cardiac function, leading to insufficient cardiac output to satisfy systemic basal metabolic demands[1]. Contemporary therapeutic approaches predominantly depend on conventional methods such as pharmacological interventions and revascularization[2,3]. However, due to the difficulty in reversing pivotal pathophysiological alterations, particularly cardiac remodeling, the clinical conditions of many patients remain inadequately ameliorated despite adherence to standardized treatment protocols. Consequently, the regenerative potential of stem cells has garnered significant attention from researchers aiming to reverse pathological cardiac remodeling. Mesenchymal stromal cells (MSCs), multipotent non-hematopoietic stromal cells, represent the most extensively studied type of stem cells for treating HF[4-7]. Previous studies have indicated that MSCs play crucial roles in reversing myocardial remodeling by producing a diverse array of substances with anti-inflammatory, antifibrotic, antiapoptotic, and proangiogenic properties via paracrine pathways[8-10]. Since the discovery of bone marrow-derived MSCs (BM-MSCs) in 1976[11], BM-MSCs have been considered the gold standard in tissue regeneration[12]. Nevertheless, the therapeutic application of BM-MSCs is significantly constrained by invasive harvesting techniques, suboptimal collection efficiency, and deterioration in quality associated with donor age and morbidity[13]. In this context, umbilical cords, which can be collected non-invasively at relatively low costs, have emerged as alternative sources for MSCs.

ADVANTAGES OF UMBILICAL CORD-DERIVED MSCS COMPARED WITH BM-MSCS

Umbilical cord-derived MSCs (UC-MSCs) offer several advantages over BM-MSCs while maintaining comparable properties in tissue repair, immunomodulation, and anti-inflammatory effects.

Minimal ethical concerns

First, in contrast to BM-MSCs, which require invasive procedures for procurement, the collection of UC-MSCs is painless and non-invasive. Moreover, as perinatal tissue, UC-MSCs are sourced from umbilical cords that are generally discarded after birth, thereby presenting minimal ethical concerns regarding their use for clinical application[14].

Higher proliferative potential

In cell passage experiments, UC-MSCs exhibited superior cumulative population doublings, reaching a maximum of 28 at passage 12, in contrast to BM-MSCs, which peaked at 22 at passage 13. These findings indicate that UC-MSCs possess greater proliferative potential than BM-MSCs[15]. This characteristic ensures an adequate yield and decreases production costs when utilized as a therapeutic product.

Superior therapeutic efficacy

The youthful cellular state of UC-MSCs also enhances their therapeutic efficacy. A recent meta-analysis by Safwan et al[16] demonstrated that UC-MSCs significantly improved the left ventricular ejection fraction (LVEF) in HF patients by 5.08% at 6 months and 2.78% at 12 months. Compared with BM-MSCs, UC-MSCs exhibit superior clonogenic, migratory, and lymphoproliferative inhibitory capabilities[17]. Additionally, UC-MSCs exhibit upregulated expression of genes associated with angiogenesis and growth and secrete a significant array of cytokines, including proangiogenic factors such as vascular endothelial growth factor (VEGF), angiopoietin-1, and transforming growth factor[18-22].

Low immunogenicity and tumorigenicity

To evaluate the safety profile of human UC-MSCs and BM-MSCs, their impact on lymphocyte proliferation rates was assessed using mixed lymphocyte reactions. The results revealed that UC-MSCs exhibit significantly lower immunogenicity than BM-MSCs[23]. The reduced immunogenicity was further substantiated by a clinical study in which patients with heart disease who received intravenous infusions of UC-MSCs did not develop alloantibodies against the administered UC-MSCs[24]. Furthermore, concerning the potential tumorigenic effects associated with pluripotent stem cells, UC-MSCs demonstrated no teratoma formation in immunodeficient mouse models, even when subjected to culture conditions conducive to tumor development[25].

THERAPEUTIC APPLICATIONS OF UC-MSCS IN HF

While UC-MSCs have been extensively utilized in treating bone-, cartilage-, skin-, and liver-related diseases, their application in cardiovascular diseases remains in its early stages[26].

UC-MSCs show cardioprotective potential in animal models

The cardioprotective effects of UC-MSCs were initially validated in a swine model of chronic myocardial ischemia. Transplantation of UC-MSCs derived from Wharton’s jelly promoted the development of vascular collateral branches, leading to a significant improvement in LVEF (61.3% in the transplanted group vs 50.3% in the control group). Further histological analysis revealed a marked reduction in fibrosis and apoptosis alongside enhanced neovascularization[27]. The inflammatory response following myocardial infarction plays a pivotal role in determining adverse ventricular remodeling and the subsequent recovery of cardiac function. In murine models of myocardial infarction, myocardial injection of UC-MSCs may increase the infiltration of CD4⁺ T cells and CD4⁺FoxP3⁺ T-regulatory cells in the injured heart via the chemokine ligand 5/chemokine receptor 5 signaling pathway, thereby blocking the excessive inflammatory response, mitigating adverse remodeling and significantly enhancing cardiac function[28]. Another study conducted using porcine models of myocardial infarction demonstrated that UC-MSCs facilitate myocardial and coronary regeneration; this was achieved by reducing inflammatory biomarkers, including tumor necrosis factor-alpha and interleukin-6, and by secreting a range of proangiogenic and growth factors, such as VEGF and platelet endothelial cell adhesion molecule-1[29]. Furthermore, intravenous administration of UC-MSCs led to increased expression of connexin 43, the most prevalent connexin in cardiac tissue, whose decreased expression is associated with increased fibrosis[29,30]. In addition to the application of UC-MSCs in ischemic cardiomyopathy-induced HF, a rat model of dilated HF induced by intraperitoneal injections of doxorubicin demonstrated that UC-MSCs increased the LVEF and reduced peripheral blood markers of HF, such as brain natriuretic peptide[31]. These findings indicate the potential protective roles of UC-MSCs in HF caused by other types of cardiac disease.

The efficacy of UC-MSCs in patients with HF

A phase I/II clinical trial assessing the safety and efficacy of intravenous infusion of UC-MSCs in patients with HF was initially published in 2017. Patients receiving UC-MSC treatment exhibited significant improvements in LVEF, cardiac function class, and Minnesota Living with Heart Failure Questionnaire scores at the 3 months, 6 months, and 12 months follow-ups compared with those in the placebo group[24]. Another comparative study evaluating the efficacy of UC-MSCs vs BM-MSCs for HF treatment revealed a significant increase in LVEF in the UC-MSC group at 6 months and 12 months post-treatment. Furthermore, the reduction in necrotic myocardium was more pronounced in the UC-MSC group, with a decrease of 7.7%, compared to a 4.5% reduction observed in the BM-MSC group[32]. Notably, neither study reported any adverse events associated with the infusion of UC-MSCs.

CHALLENGES IN THE APPLICATION OF UC-MSCS

Transferring UC-MSCs from the laboratory to clinical use still presents challenges, primarily due to inadequate quality control and some discrepancies observed in clinical trials. To facilitate the clinical implementation of US-MSC therapy, it is imperative to establish standardized protocols and rigorous quality control measurements.

Standardized separation and evaluation of UC-MSCs

Human UC-MSCs are typically isolated from Wharton’s jelly within the umbilical cord. However, due to the unclear histological demarcation of compartments within the umbilical cord, derivation protocols involving different compartments may result in mixed heterogeneous stem cell populations, complicating the assessment of investigations[20]. Therefore, standardized protocols for UC-MSC derivation are essential to produce defined or minimally heterogeneous stem cell populations. Current isolation methods, including enzymatic and explant techniques, are continuously investigated by researchers to identify the most suitable enzyme types, explant techniques, and culture conditions that may effectively control the UC-MSC heterogeneity[33]. Furthermore, there is a pressing need to develop sophisticated evaluation models capable of precisely predicting the efficacy of UC-MSCs from various sources. Moreover, discovering specific biomarkers that consistently identify UC-MSCs with optimal in vivo efficacy remains an unresolved challenge.

Established culture system for clinical-grade UC-MSCs

The post-extraction culture environment has been demonstrated to significantly influence the properties of UC-MSCs, with notable variations observed in the biological characteristics of cells produced under different conditions[34]. Consequently, establishing a culture system that can reliably produce clinical-grade UC-MSCs on a large scale is critical for broadening their applications. Currently, mature and standardized culture systems are deficient; thus, further investigations into safer and more efficient protocols for culture, preservation, and expansion are necessary. Alternatively, directly utilizing UC-MSC products, facilitating easier quality control, may represent another viable approach to achieving standardized production. On the other hand, researchers have reported that oxidative stress associated with cell isolation, culture, and transplantation processes can trigger cell death and apoptosis in MSCs, thereby limiting their therapeutic efficacy. By artificially optimizing the secretion state of extracted UC-MSCs, their secretome - comprising numerous anti-inflammatory, antifibrotic, antiapoptotic, and proangiogenic factors - can also be harnessed to treat HF. Therefore, utilizing the secretome derived from optimally pretreated MSCs has been proposed as an alternative to direct cell transplantation[35]. This cell-free therapy may offer another strategy for achieving stable efficacy of UC-MSCs in future applications.

Survival rate of UC-MSCs after transplantation

The low survival rate after transplantation is a problem faced by any kind of MSC and is one of the key reasons for the blockage of the cardiac repair effect of MSCs. Several strategies have been explored to improve UC-MSC survival, and one of the most important strategies is the optimal delivery strategy for UC-MSCs in clinical applications. The commonly employed methods are intramyocardial injection and intracoronary delivery, which often result in low survival rates and inaccurate localization of implant cells[36]. Biological scaffolds have been proposed to enhance the precise localization of UC-MSCs on cardiac tissues and to address the limitations associated with injected grafts[37,38]. However, the prolonged presence of a scaffold can induce inflammation and foreign body reactions, thereby partially diminishing the efficacy. To circumvent these issues, a scaffold-free cell sheet has been engineered to facilitate stem cell delivery while preserving the integrity of intercellular contacts and the extracellular matrix through simple temperature modulation[39]. This technology has shown considerable potential in the application of UC-MSCs. Specifically, the retention and survival rates of UC-MSC sheets in the infarcted hearts of mice were significantly greater than those of cell suspensions[40]. Furthermore, the proliferation rate of UC-MSC cell sheets surpassed that of BM-MSCs and other cell sheets[41]. The efficacy of this approach was also corroborated in a rat model of HF[42]. In addition, a hydrogel derived from bovine collagen tissue has been developed to improve the delivery of UC-MSCs in patients with myocardial infarction. The safety and feasibility of this approach have also been validated through a randomized controlled study[43].

Concurrently, researchers have employed genetic engineering techniques to alter the characteristics of MSCs to increase their viability. Genetic modification of protein kinase B has been shown to increase MSC resistance to apoptosis and augment their capacity to secrete paracrine factors such as VEGF, insulin-like growth factor-1, and fibroblast growth factor 2[44,45]. Additionally, overexpression of lipocalin 2 in UC-MSCs has been shown to improve cell survival post-transplantation by enhancing their cellular adhesion capabilities[46]. Despite these promising findings, the clinical translation of UC-MSCs for treating HF remains nascent. As of August 2024, a search for UC-MSCs and HF on ClinicalTrials.gov yielded fewer than 10 registered clinical trials. The extant studies are predominantly phase I and II trials, with few participants and limited conclusive results. Further clinical trials are ongoing, and attention should be given to the potential for adverse effects with UC-MSC application, although they have not yet been reported. Rigorously designed phase III trials are urgently needed to further explore the impact of different UC-MSC delivery strategies on HF treatment. Moreover, current clinical studies of MSCs in the cardiovascular field have focused predominantly on ischemic heart disease[47,48], highlighting a gap in research regarding the efficacy of UC-MSCs in HF caused by other cardiac conditions and their comparative efficacy across different diseases. Further investigation into the efficacy of UC-MSCs in HF patients with diverse etiologies and classifications should be considered a key area for future research.

CONCLUSION

As an emerging treatment for HF, UC-MSCs are notable for their painless and non-invasive collection, low immunogenicity and tumorigenicity, and high proliferative and migratory capacities. Extensive preclinical studies and several clinical trials have demonstrated that UC-MSCs ameliorate adverse cardiac remodeling, enhance cardiac function, and improve LVEF in pathological hearts through various mechanisms, such as promoting angiogenesis, inhibiting inflammation, and reducing fibrosis and apoptosis. Despite ongoing advancements, significant challenges remain in the clinical translation of UC-MSCs to treat HF. Establishing standardized protocols for the isolation, culture, and delivery of UC-MSCs is crucial to enhance their therapeutic efficacy. Concurrently, rigorously designed clinical trials are essential to ensure the safety of UC-MSC applications. Moreover, exploring the effects of UC-MSCs across diverse types of heart disease and conducting comparative analyses of their effectiveness could substantially broaden the therapeutic scope of UC-MSC therapy.