From bench to bedside: translating mesenchymal stem cell therapies through preclinical and clinical evidence

Abstract

Mesenchymal stem cells (MSCs) are emerging as a powerful tool in regenerative medicine due to their ability to differentiate into mesenchymal lineages, such as bone, cartilage, and fat, along with their low immunogenicity and strong immunomodulatory properties. Unlike traditional cell therapies that rely on engraftment, MSCs primarily function through paracrine signaling-secreting bioactive molecules like vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-β), and exosomes. These factors contribute to tissue repair, promote angiogenesis, and modulate immune responses in damaged or inflamed tissues. Recent studies have identified mitochondrial transfer as a novel therapeutic mechanism, where MSCs donate mitochondria to injured cells, restoring their bioenergetic function. This has expanded the therapeutic potential of MSCs to include conditions such as acute respiratory distress syndrome (ARDS) and myocardial ischemia. Clinically, MSCs have shown efficacy in diseases like graft-versus-host disease (GVHD), Crohn's disease, and COVID-19. Trials such as REMODEL and REMEDY have demonstrated improved clinical outcomes, further validating MSC-based interventions. However, several challenges remain, including variability in cell potency, poor engraftment, and inconsistent results across clinical trials. Advances in genetic engineering such as CRISPR-modified MSCs and biomaterial scaffolds are being developed to enhance therapeutic efficacy and cell survival. Additionally, AI-driven platforms are being utilized to personalize MSC therapy and optimize cell selection. Innovative approaches like 3D bioprinting and scalable manufacturing are paving the way for more consistent and precise therapies. Moving forward, the integration of mechanistic insights with robust quality control and regulatory frameworks essential to translating MSC therapies from bench to bedside and ensuring their reliable application in clinical practice.

Keywords: clinical evidence; immunomodulation; mesenchymal stem cells (MSCs); paracrine signaling; regenerative medicine; regulatory.

FIGURE 1

Sources of Mesenchymal Stem Cells (MSCs) The figure illustrates various tissue sources for deriving MSCs, including bone marrow, peripheral blood, adipose tissue, dental pulp, placenta, umbilical cord, synovial fluid, menstrual blood and hair follicle cells. These sources highlight the diverse origins of MSCs, which are widely studied for their regenerative and therapeutic potential.

FIGURE 2

Multifunctional Mechanisms of Mesenchymal Stem Cells (MSCs) in Regenerative Therapy. The figure illustrates four key mechanisms through which MSCs exert their therapeutic effects: (A) Paracrine Activity of MSCs: MSCs secrete a variety of bioactive molecules, including anti-inflammatory cytokines (IL-6, IL-10, IL-1Ra), growth factors (VEGF, TGF-β), and tissue-protective factors (TSG-6), which modulate immune responses and promote tissue repair. (B) Differentiation Potential of MSCs: MSCs possess the ability to differentiate into multiple cell lineages (e.g., osteocytes, chondrocytes, adipocytes), contributing directly to tissue regeneration. The secretome of MSCs further supports this process by creating a regenerative microenvironment. (C) Organelle Transfer: MSCs can transfer functional organelles, such as mitochondria, to damaged cells, restoring cellular metabolism and enhancing survival in target tissues. (D) Transfer of Molecules by Exosomes and Microvesicles: MSCs release exosomes and microvesicles containing proteins, nucleic acids, and signaling molecules, which are taken up by recipient cells to mediate therapeutic effects, including immune modulation and tissue repair.