A systematic review of preclinical studies on therapeutic potential of mesenchymal stem/stromal cells and their secretome in bacterial infections

Abstract

Background  Bacterial infections are a globally growing health issue, with an estimated 7.7 million deaths attributed to these infections worldwide. These life-threatening infections, primarily linked to antimicrobial resistance, are difficult to treat, and the growing reliance on last-resort antibiotics is exacerbating the problem. For this reason, numerous preclinical studies have been conducted using mesenchymal stem/stromal cells (MSCs) and their secretome as an alternative new therapeutic strategy for treating bacterial infections. However, these studies exhibit substantial disparities, often due to the lack of a consensus definition for MSCs and the broad variability in their reported characteristics. Thus, the purpose of this systematic review was to summarize studies that have used various sources of human MSCs and their secretome to treat bacterial infection in rodent models, to present an overview of evidence to proceed with clinical studies. Methods  This systematic review was registered with PROSPERO and conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Using search terms related to “mesenchymal stem cells”, “mesenchymal stromal cells” as recommended by ISCT, “bacterial infections”, and “therapy”, candidate articles were identified through the PubMed database, and data were gathered using a narrative approach. Results  Of the 517 articles retrieved, only thirty-seven studies met the inclusion criteria, and their analysis revealed several main findings. Human MSCs demonstrated positive effects mainly in decreasing bacterial load, reducing injuries, and improving the overall survival rate in rodents, with bone marrow-derived MSCs being the most used and effective type. All studies demonstrated that MSCs and their secretome can modify and enhance the immune response in rodents after bacterial infection. Conclusions  This study showed that employing both stem cell-based and cell-free therapies for the treatment of bacterial infections has significant results in preclinical studies, offering promising potential as alternative treatment options. However, the findings are based solely on rodent models and the absence of donor-related investigations, necessitating further research to translate these findings into clinical applications.

1. Introduction

Worldwide, an estimated 7.7 million deaths have been associated with bacterial infections, making them the second leading cause of death [1]. These infections are becoming increasingly challenging to manage due to the aggravation of the antimicrobial resistance (AMR) issue. The World Health Organization (WHO) has forewarned that drug-resistant infections could lead to 10 million deaths annually by 2050 if no new treatment strategies are developed [2]. As it is known, AMR is a natural process that occurs when microorganisms evolve and no longer respond to antibiotics to which they were previously susceptible and treated with [3]. This process is escalating due to several factors, including the overuse and misuse of antibiotics, inadequate hygiene, poor infection control measures in healthcare settings and communities, and the lack of access to healthcare services [4].

Without a doubt, both resistant forms of Gram-positive bacteria such as Staphylococcus aureus, and Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa, play a significant role in worsening the burden of infection, increasing morbidity and mortality rates, and complicating treatment protocols within communities and healthcare facilities. Despite advances in pharmacotherapy for bacterial infections, antibiotics remain associated with adverse side effects, necessitating an urgent need for novel therapeutic strategies that can combat bacterial infections without contributing to resistance. A wide variety of candidate therapies have been proposed, including bacteriophage therapy, immunotherapies, antimicrobial peptides, nanotechnology-based approaches, nutraceuticals, and cellular therapies [5–9].

Mesenchymal stromal cells (MSCs) are adult multipotent cells that have attracted considerable interest as a potential treatment for a wide range of diseases including bacterial infections [10]. MSCs were first isolated from the bone marrow and have since been found in a diverse range of tissues.