The therapeutic potential of mesenchymal stem cells in intestinal diseases: from mechanisms to clinical translation

Abstract

Current therapeutic interventions for intestinal pathologies, including anti-inflammatory agents, immunosuppressants, and surgical procedures, frequently incur substantial adverse effects, elevated recurrence rates, and suboptimal tissue regeneration. Cellular therapy has emerged as a paradigm-shifting strategy, capitalizing on regenerative potential and immunomodulatory properties. Mesenchymal stem cells (MSCs), distinguished by their potent immunoregulatory capacity and multipotent differentiation plasticity, have recently demonstrated remarkable therapeutic promise in inflammatory bowel disease (IBD), ischemia–reperfusion injury, oncological interventions, and radio-chemotherapy-induced complications. This systematic review critically evaluates MSC biological characteristics, clinical translation progress, and cutting-edge advancements in tissue engineering applications. Mechanistic insights into MSC-mediated intestinal repair are elucidated, with particular emphasis on emerging evidence suggesting MSC-derived exosomes may modulate ZBP1-associated H3K27 acetylation to attenuate intestinal epithelial apoptosis—a novel epigenetic regulatory axis for gastrointestinal restitution. Future translational trajectories and clinical implementation challenges are comprehensively discussed.

1. Introduction

Mesenchymal stem cells (MSCs) are a type of multipotent adult stem cell initially isolated from bone marrow and subsequently identified in diverse tissues, including adipose tissue, umbilical cord blood, placenta, and dental pulp [1] (Table 1). The term "MSCs" was first formally defined by Caplan in 1991 [2]. Prior to this designation, bone marrow-derived fibroblasts exhibiting osteogenic and chondrogenic differentiation capacities were erroneously classified as MSCs [3]. Notably, the terminology "mesenchymal stromal cells" frequently coexists with "mesenchymal stem cells" in related literature. According to nomenclature guidelines established by the International Society for Cell Therapy (ISCT), both terms are abbreviated as MSCs and are considered functionally equivalent in most experimental contexts [4]. In 2006, ISCT established three minimal defining criteria for human MSCs: 1. Adherence to plastic under standard culture conditions; 2. Positive expression (>95%) of surface markers CD73, CD90, and CD105, with negative expression (<2%) of HLA-DR, CD14, CD34, CD45, CD116, CD79α, or CD19; 3. Multilineage differentiation potential into osteoblasts, adipocytes, and chondrocytes under specific induction conditions [5]. Beyond their well-characterized differentiation capabilities, MSCs exhibit immunomodulatory properties, tissue-specific homing capacity, paracrine signaling functions, and remarkable tissue repair potential. These attributes collectively position MSCs as promising therapeutic agents for immune-mediated disorders and tissue regeneration applications.

Intestinal pathologies are commonly categorized into four major types: inflammatory disorders (such as Crohn’s disease and ulcerative colitis), ischemic conditions (such as mesenteric ischemia/reperfusion injury), neoplastic diseases (such as colorectal cancer), and iatrogenic injuries (such as radiation/chemotherapy-induced enteritis). The disruption of intestinal barrier integrity constitutes the core pathological mechanism underlying these conditions. The intestinal barrier comprises mechanical, chemical, immune, and microbial components, with intestinal epithelial cells serving as its fundamental constituents. These polarized columnar epithelial cells form a continuous monolayer lining the intestinal lumen, consisting of absorptive enterocytes, mucin-secreting goblet cells, antimicrobial Paneth cells, and hormone-producing enteroendocrine cells, collectively orchestrating nutrient absorption, mucosal protection, and immune surveillance [6]. Epithelial barrier integrity is maintained through intercellular tight junction complexes and continuous cellular renewal (Table 2). Notably, intestinal epithelial cells exhibit remarka