Current Good Manufacturing Practice (GMP) standards for cell therapies assess identity, viability, sterility, and genetic stability. For extracellular vesicle (EV) products, the Minimal Information for Studies of Extracellular Vesicles (MISEV2023) guidelines recommend evaluating particle size, concentration, markers, morphology, contaminants, endotoxin, and functional activity. However, these assessments rarely examine protein homeostasis in donor cells. During ex vivo expansion, stem cells may develop senescence, reduced proteasomal activity, impaired autophagy, and weakened heat shock responses, potentially allowing damaged proteins and inflammatory factors to accumulate. Since EV cargo reflects the condition of parent cells, these defects may affect recipient cells, highlighting the need for improved proteostatic quality control in mesenchymal stromal cell (MSC) and induced pluripotent stem cell (iPSC)-derived products.

Published online on June 9, 2026, in Regenesis Repair Rehabilitation (DOI: 10.1016/j.rerere.2026.06.004), a review by researchers from the University of Manitoba, Canada, and Zhujiang Hospital of Southern Medical University, China, examines proteotoxic stress in stem cell therapies. The authors highlight cellular senescence, EV cargo, and superoxide dismutase 1 (SOD1), emphasizing that protein quality control is not routinely included in current product-release standards. They recommend improved cell-source selection, senescence screening, EV proteomic profiling, and pre-transplantation cargo sanitization.

The review describes how repeated cell expansion can accelerate senescence, characterized by elevated p16 and p21 expression, increased senescence-associated β-galactosidase (SA-β-Gal) activity, persistent DNA damage, and the senescence-associated secretory phenotype (SASP). In mesenchymal stromal cells, declining heat shock factor 1 (HSF1) activity and reduced heat shock protein 70 (Hsp70) responses may weaken cellular protection. In neural stem cells, oxidized SOD1 has been associated with aging-related changes and mitochondrial-derived vesicle formation. These vesicles may transport damaged proteins and contribute to mitochondrial dysfunction and senescence in recipient cells. The review also discusses misfolded SOD1, TDP-43, and α-synuclein as potential contributors to protein aggregation, alongside declining proteasomal activity and disrupted autophagic flux.

The authors argue that proteostatic fitness should be considered an important product-release attribute, as therapies may pass conventional identity, viability, and sterility tests while retaining protein-handling defects. They propose quantitative senescence thresholds and EV cargo profiling, including assays for misfolded or oxidized SOD1 in products intended for neurodegenerative applications. The review also discusses CT4 peptide-based cargo sanitization, which has shown promising results in preclinical research, although its safety, scalability, cost, immunogenicity, and off-target effects require further investigation.

If validated, these approaches could strengthen quality control for MSC- and iPSC-derived therapies targeting acute graft-versus-host disease, cardiac repair, orthopedic injuries, renal disease, and amyotrophic lateral sclerosis (ALS). The authors call for multi-site validation and harmonized testing standards to improve product consistency, safety, and therapeutic reliability.

Source: https://www.news-medical.net/news/20261022/Stem-cell-therapies-may-need-new-protein-quality-control-standards.aspx