Hurdles to overcome for mesenchymal stem cell translation from bench to bedside

Abstract

Mesenchymal stem or stromal cells (MSCs) are among the most extensively studied cell populations in regenerative medicine due to their multipotent differentiation potential, secretion of trophic factors, and immunomodulatory effects. Over the past two decades, preclinical studies have demonstrated encouraging results across musculoskeletal, cardiovascular, neurological, and immune-mediated disorders. However, the translation of MSCs from the laboratory to routine clinical practice remains hindered by unresolved scientific, technical, and regulatory challenges. This review provides a critical appraisal of these hurdles, organized across three major stages of translation: In vitro research, in vivo animal studies, and clinical application. In vitro issues include the heterogeneity of isolation techniques, replicative senescence during expansion, genetic and epigenetic instability, and the need for xeno-free, standardized culture platforms. In vivo challenges arise from poor cell survival, low engraftment rates, off-target migration, and microenvironmental influences that shape therapeutic outcomes. Clinical translation introduces additional complexity, including inter-patient variability, large-scale manufacturing difficulties, stringent regulatory compliance, high production costs, and the absence of harmonized potency assays. Solutions under exploration include the use of automated bioreactors, biomimetic scaffolds, hypoxic preconditioning, extracellular vesicle-based therapies, and international standardization efforts. Addressing these hurdles through multidisciplinary collaboration is essential for MSC-based therapies to become reliable, safe, and accessible regenerative treatments.

Keywords: Regenerative medicine; Clinical translation; Stem cell expansion; Scaffolds; Immunomodulation; Good manufacturing practice

Core Tip: Regenerative medicine has been practiced in a variety of settings for decades. It is a multidisciplinary branch of medicine that aims at replacing degenerated cells or regenerating new human cells, tissues, or organs that have been lost or damaged due to the effects of aging, illness, or congenital defects. The main objective of regenerative medicines is to restore normal functions of the cells or tissues in patients affected by degenerative disorders. Mesenchymal stem cells (MSCs) have the potential to cure the most critical regions or take over the function of a wounded organ that is considered beyond repair using conventional therapies. In the last two decades, thousands of in vitro, in vivo, and clinical trials have been conducted using MSCs. Though the regenerative potential of MSCs has been extensively studied, there are still a lot of challenges that need to be addressed for their successful translation from bench to bedside.