Mesenchymal Stromal Cell Secretome and Its Key Bioactive Metabolites Induce Long‐Term Neuroprotection After Traumatic Brain Injury in Mice

The severe and long-term consequences of traumatic brain injury (TBI) highlight the urgent need for effective neuroprotective therapies. Mesenchymal stromal cells (MSCs) show promise in TBI treatment through their secretome (conditioned media, CM). A low-molecular-weight (<700 Da) CM fraction with neuroprotective effects comparable to total CM after acute brain injury in vitro is previously identified. Here, it is aimed at identifying key bioactive factors, reconstituting them into a synthetic cocktail (SYNT), and evaluating its efficacy in TBI models. Metabolomic profiling identified three prostaglandins and kynurenine, which are used to create SYNT. The SYNT formulation reduced cell death, neuronal damage, and induced protective gene expression changes associated with neuronal protection and microglia modulation toward beneficial phenotype after TBI in vitro. In vivo, SYNT conferred similar long-term functional benefits as CM, improving sensorimotor function up to 6 months and memory preservation at 4 months compared to saline-treated animals, though only CM reduced contusion volume at 5 months. Both treatments modulated neuroinflammation, evidenced by reduced microglial activation and astrogliosis in the pericontusional tissue at 6 months. These findings demonstrate the neuroprotective effects of MSC-secretome treatment in TBI and highlight prostaglandins and kynurenine as key mediators of this response. The findings lay the groundwork for developing a standardized, cell-free therapeutic strategy for TBI based on MSC derivatives.

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Publication Details

Journal
Advanced Science
Published
2025-06-19
DOI
https://doi.org/10.1002/advs.202415508
Citations
4
Primary Topic
Mesenchymal stem cell research
Type
article
Field-Weighted Citation Impact
6.50
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Mesenchymal Stromal Cell Secretome and Its Key Bioactive Metabolites Induce Long‐Term Neuroprotection After Traumatic Brain Injury in Mice

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4 citations
Advanced Science
Mesenchymal stem cell research
6.50
article

Mesenchymal Stromal Cell Secretome and Its Key Bioactive Metabolites Induce Long‐Term Neuroprotection After Traumatic Brain Injury in Mice

Giulia De Simone, Rosaria Pascente, Laura Brunelli, Luca Guarrera, Elisa R. Zanier, Roberta Pastorelli, Francesca Tribuzio, Enrico Caruso, Martina Bruna Violatto, L D Loose, Cristina Banfi, Marco Bolis, Maria Chiara Trolese, C Bertani, Marta Magatti, Fabrizio Ortolano, Edoardo Mazzone, Antonietta Rosa Silini, Ornella Parolini, Giovanni Nattino, Paolo Bigini, Edoardo Micotti, Francesca Pischiutta, Federico Moro, Fabiola Signorini
article en
4 citations

Abstract

The severe and long-term consequences of traumatic brain injury (TBI) highlight the urgent need for effective neuroprotective therapies. Mesenchymal stromal cells (MSCs) show promise in TBI treatment through their secretome (conditioned media, CM). A low-molecular-weight (<700 Da) CM fraction with neuroprotective effects comparable to total CM after acute brain injury in vitro is previously identified. Here, it is aimed at identifying key bioactive factors, reconstituting them into a synthetic cocktail (SYNT), and evaluating its efficacy in TBI models. Metabolomic profiling identified three prostaglandins and kynurenine, which are used to create SYNT. The SYNT formulation reduced cell death, neuronal damage, and induced protective gene expression changes associated with neuronal protection and microglia modulation toward beneficial phenotype after TBI in vitro. In vivo, SYNT conferred similar long-term functional benefits as CM, improving sensorimotor function up to 6 months and memory preservation at 4 months compared to saline-treated animals, though only CM reduced contusion volume at 5 months. Both treatments modulated neuroinflammation, evidenced by reduced microglial activation and astrogliosis in the pericontusional tissue at 6 months. These findings demonstrate the neuroprotective effects of MSC-secretome treatment in TBI and highlight prostaglandins and kynurenine as key mediators of this response. The findings lay the groundwork for developing a standardized, cell-free therapeutic strategy for TBI based on MSC derivatives.

Advanced ScienceVol. 12(29)
Università Cattolica del Sacro Cuore (IT), Mario Negri Institute for Pharmacological Research (IT), Casa Sollievo della Sofferenza (IT), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Centro Cardiologico Monzino (IT), Fondazione Poliambulanza Istituto Ospedaliero (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT)
Good health and well-being
Openalex Percentile: Top 3%
Mesenchymal stem cell research
6.50
DOIOpen Access PDFOpenAlex
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