Stem cells have long been considered the holy grail of regenerative medicine. For decades, the prevailing belief was that these cells worked by physically replacing damaged tissues. However, a comprehensive new review published in Science Bulletin reveals a dramatic paradigm shift in the field: the true healing power of Mesenchymal Stem/Stromal Cells (MSCs) lies not in their ability to become new tissue, but in their capacity to act as master regulators of the body's internal microenvironment.
Initially, research on MSCs focused on their multilineage differentiation potential. However, accumulating preclinical and clinical evidence confirms that a simple cell supplementation strategy fails to achieve genuine tissue regeneration. Instead, the review highlights that MSCs function as a crucial "regulatory hub." Through powerful immunomodulatory and paracrine properties, they drive the host's injured tissues to re-enter a development-like state, thereby activating the organism's intrinsic regenerative plasticity.
Professor Songtao Shi, the corresponding author of the study, highlighted a standout concept in the review: the unique, environment-dependent dynamic regulatory capacity of MSCs. “Unlike conventional drugs that offer fixed, single-target effects—such as simple anti-inflammatory or pro-proliferative effects alone—MSCs act as smart, dynamic regulators”. Professor Shi said. “They can sense changes in the host microenvironment in real-time and dynamically adjust their own regulatory phenotypes and secretory factors to rectify imbalanced biological processes. This “dynamic balance regulation” is the core advantage of MSCs, making their regulatory effects more consistent with the physiological needs of the host”.
At the forefront of this rapidly expanding therapeutic frontier is the transition toward cell-free therapies. The review notes that when transplanted, viable MSCs rapidly undergo extensive apoptosis in the host microenvironment. During this process, they release apoptotic extracellular vesicles (apoVs) that serve as indispensable therapeutic mediators. Harnessing these cell-free signals from programmed cell death offers a novel avenue to amplify efficacy while circumventing the safety, senescence, and quality control challenges associated with living cell therapies.
As these breakthrough therapies advance toward clinical translation, the review emphasizes the critical importance of navigating the regulatory landscape. While some MSC products have received approval in Europe and Japan, they face rigorous biological product pathways (IND/BLA) under the US FDA. Furthermore, the clinical translation of emerging MSC-EVs will heavily rely on stringent Chemistry, Manufacturing, and Controls (CMC) standards and adherence to updated international guidelines (such as MISEV2023) to establish standardized manufacturing and release criteria.
The study was led by first author Dr. Manjin Zhang, a postdoctoral researcher at Southern Medical University and the South China Center of Craniofacial Stem Cell Research. The co-authors of the study are also from the South China Center of Craniofacial Stem Cell Research. The findings were published in the premier multidisciplinary journal Science Bulletin .
Science Bulletin
Literature review