The stromal cell microenvironment and its effect on cell therapy: a review of the literature

Abstract

Mesenchymal stromal cells (MSCs) are central to regenerative medicine due to their multipotent differentiation capacity and, predominantly, their paracrine-mediated immunomodulatory and reparative effects. Increasing evidence indicates that systemic and local microenvironmental alterations associated with metabolic diseases critically influence MSC function and therapeutic efficacy. This review provides an integrated analysis of how diabetes and hyperglycemia, obesity, hypoxia induced cellular senescence modulate MSC biology and secretome composition, with emphasis on extracellular vesicles (EVs) as key effectors of MSC-mediated tissue repair. Chronic hyperglycemia disrupts MSC homeostasis through AGE–RAGE signaling, oxidative stress, and inflammatory pathway activation, leading to impaired proliferation, differentiation, immunomodulation, and qualitative changes in EV cargo. Obesity further exacerbates MSC dysfunction by inducing mitochondrial impairment, endoplasmic reticulum stress, senescence, and a shift toward a pro-inflammatory and less regenerative secretory profile, including altered cytokine release and microRNA content in EVs. In contrast, controlled hypoxia emerges as a critical regulator that preserves MSC stemness, enhances metabolic adaptation, and potentiates paracrine and EV-mediated regenerative effects via HIF-1α–dependent mechanisms, although excessive or poorly controlled hypoxia may promote cellular damage and senescence. Cellular senescence represents a convergent outcome of these adverse microenvironmental conditions, profoundly impairing MSC activity and reshaping the secretome toward a senescence-associated secretory phenotype that propagates inflammation and limits tissue regeneration. Collectively, the evidence highlights the need to consider microenvironmental conditioning, and senescence in MSC- autologous transplantation or EV-based therapies. Strategies aimed at restoring MSC metabolic fitness, optimizing culture conditions, and modulating the secretome are essential to improve the consistency and efficacy of regenerative interventions.