Protection of Brain Injury by Amniotic Mesenchymal Stromal Cell-Secreted Metabolites

Francesca Pischiutta, Laura Brunelli, Pietro Romele, Antonietta Silini, Eliana Sammali, Lara Paracchini, Sergio Marchini, Laura Talamini, Paolo Bigini, Giorgio Battista Boncoraglio, Roberta Pastorelli, Maria Grazia De Simoni, O. Parolini, Elisa Roncati Zanier

Research output: Contribution to journalArticle

Abstract

OBJECTIVES:: To define the features of human amniotic mesenchymal stromal cell secretome and its protective properties in experimental models of acute brain injury. DESIGN:: Prospective experimental study. SETTING:: Laboratory research. SUBJECTS:: C57Bl/6 mice. INTERVENTIONS:: Mice subjected to sham or traumatic brain injury by controlled cortical impact received human amniotic mesenchymal stromal cells or phosphate-buffered saline infused intracerebroventricularly or intravenously 24 hours after injury. Organotypic cortical brain slices exposed to ischemic injury by oxygen-glucose deprivation were treated with human amniotic mesenchymal stromal cells or with their secretome (conditioned medium) in a transwell system. MEASUREMENTS AND MAIN RESULTS:: Traumatic brain injured mice receiving human amniotic mesenchymal stromal cells intravenously or intracerebroventricularly showed early and lasting functional and anatomical brain protection. cortical slices injured by oxigen-glucose deprivation and treated with human amniotic mesenchymal stromal cells or conditioned medium showed comparable protective effects (neuronal rescue, promotion of M2 microglia polarization, induction of trophic factors) indicating that the exposure of human amniotic mesenchymal stromal cells to the injured tissue is not necessary for the release of bioactive factors. Using sequential size-exclusion and gel-filtration chromatography, we identified a conditioned medium subfraction, which specifically displays these highly protective properties and we found that this fraction was rich in bioactive molecules with molecular weight smaller than 700 Da. Quantitative RNA analysis and mass spectrometry-based peptidomics showed that the active factors are not proteins or RNAs. The metabolomic profiling of six metabolic classes identified a list of molecules whose abundance was selectively elevated in the active conditioned medium fraction. CONCLUSIONS:: Human amniotic mesenchymal stromal cell-secreted factors protect the brain after acute injury. Importantly, a fraction rich in metabolites, and containing neither proteic nor ribonucleic molecules was protective. This study indicates the profiling of protective factors that could be useful in cell-free therapeutic approaches for acute brain injury.

Original languageEnglish
Pages (from-to)e1118-e1131
JournalCritical Care Medicine
Volume44
DOIs
Publication statusPublished - 2016

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Mesenchymal Stromal Cells
Brain Injuries
Conditioned Culture Medium
Brain
RNA
Glucose
Metabolomics
Wounds and Injuries
Microglia
Gel Chromatography
Mass Spectrometry
Theoretical Models
Molecular Weight
Phosphates
Prospective Studies
Oxygen
Research
Proteins

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Protection of Brain Injury by Amniotic Mesenchymal Stromal Cell-Secreted Metabolites. / Pischiutta, Francesca; Brunelli, Laura; Romele, Pietro; Silini, Antonietta; Sammali, Eliana; Paracchini, Lara; Marchini, Sergio; Talamini, Laura; Bigini, Paolo; Boncoraglio, Giorgio Battista; Pastorelli, Roberta; De Simoni, Maria Grazia; Parolini, O.; Roncati Zanier, Elisa.

In: Critical Care Medicine, Vol. 44, 2016, p. e1118-e1131.

Research output: Contribution to journalArticle

Pischiutta F, Brunelli L, Romele P, Silini A, Sammali E, Paracchini L et al. Protection of Brain Injury by Amniotic Mesenchymal Stromal Cell-Secreted Metabolites. Critical Care Medicine. 2016;44:e1118-e1131. https://doi.org/10.1097/CCM.0000000000001864
Pischiutta, Francesca ; Brunelli, Laura ; Romele, Pietro ; Silini, Antonietta ; Sammali, Eliana ; Paracchini, Lara ; Marchini, Sergio ; Talamini, Laura ; Bigini, Paolo ; Boncoraglio, Giorgio Battista ; Pastorelli, Roberta ; De Simoni, Maria Grazia ; Parolini, O. ; Roncati Zanier, Elisa. / Protection of Brain Injury by Amniotic Mesenchymal Stromal Cell-Secreted Metabolites. In: Critical Care Medicine. 2016 ; Vol. 44. pp. e1118-e1131.
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AU - Pischiutta, Francesca

AU - Brunelli, Laura

AU - Romele, Pietro

AU - Silini, Antonietta

AU - Sammali, Eliana

AU - Paracchini, Lara

AU - Marchini, Sergio

AU - Talamini, Laura

AU - Bigini, Paolo

AU - Boncoraglio, Giorgio Battista

AU - Pastorelli, Roberta

AU - De Simoni, Maria Grazia

AU - Parolini, O.

AU - Roncati Zanier, Elisa

PY - 2016

Y1 - 2016

N2 - OBJECTIVES:: To define the features of human amniotic mesenchymal stromal cell secretome and its protective properties in experimental models of acute brain injury. DESIGN:: Prospective experimental study. SETTING:: Laboratory research. SUBJECTS:: C57Bl/6 mice. INTERVENTIONS:: Mice subjected to sham or traumatic brain injury by controlled cortical impact received human amniotic mesenchymal stromal cells or phosphate-buffered saline infused intracerebroventricularly or intravenously 24 hours after injury. Organotypic cortical brain slices exposed to ischemic injury by oxygen-glucose deprivation were treated with human amniotic mesenchymal stromal cells or with their secretome (conditioned medium) in a transwell system. MEASUREMENTS AND MAIN RESULTS:: Traumatic brain injured mice receiving human amniotic mesenchymal stromal cells intravenously or intracerebroventricularly showed early and lasting functional and anatomical brain protection. cortical slices injured by oxigen-glucose deprivation and treated with human amniotic mesenchymal stromal cells or conditioned medium showed comparable protective effects (neuronal rescue, promotion of M2 microglia polarization, induction of trophic factors) indicating that the exposure of human amniotic mesenchymal stromal cells to the injured tissue is not necessary for the release of bioactive factors. Using sequential size-exclusion and gel-filtration chromatography, we identified a conditioned medium subfraction, which specifically displays these highly protective properties and we found that this fraction was rich in bioactive molecules with molecular weight smaller than 700 Da. Quantitative RNA analysis and mass spectrometry-based peptidomics showed that the active factors are not proteins or RNAs. The metabolomic profiling of six metabolic classes identified a list of molecules whose abundance was selectively elevated in the active conditioned medium fraction. CONCLUSIONS:: Human amniotic mesenchymal stromal cell-secreted factors protect the brain after acute injury. Importantly, a fraction rich in metabolites, and containing neither proteic nor ribonucleic molecules was protective. This study indicates the profiling of protective factors that could be useful in cell-free therapeutic approaches for acute brain injury.

AB - OBJECTIVES:: To define the features of human amniotic mesenchymal stromal cell secretome and its protective properties in experimental models of acute brain injury. DESIGN:: Prospective experimental study. SETTING:: Laboratory research. SUBJECTS:: C57Bl/6 mice. INTERVENTIONS:: Mice subjected to sham or traumatic brain injury by controlled cortical impact received human amniotic mesenchymal stromal cells or phosphate-buffered saline infused intracerebroventricularly or intravenously 24 hours after injury. Organotypic cortical brain slices exposed to ischemic injury by oxygen-glucose deprivation were treated with human amniotic mesenchymal stromal cells or with their secretome (conditioned medium) in a transwell system. MEASUREMENTS AND MAIN RESULTS:: Traumatic brain injured mice receiving human amniotic mesenchymal stromal cells intravenously or intracerebroventricularly showed early and lasting functional and anatomical brain protection. cortical slices injured by oxigen-glucose deprivation and treated with human amniotic mesenchymal stromal cells or conditioned medium showed comparable protective effects (neuronal rescue, promotion of M2 microglia polarization, induction of trophic factors) indicating that the exposure of human amniotic mesenchymal stromal cells to the injured tissue is not necessary for the release of bioactive factors. Using sequential size-exclusion and gel-filtration chromatography, we identified a conditioned medium subfraction, which specifically displays these highly protective properties and we found that this fraction was rich in bioactive molecules with molecular weight smaller than 700 Da. Quantitative RNA analysis and mass spectrometry-based peptidomics showed that the active factors are not proteins or RNAs. The metabolomic profiling of six metabolic classes identified a list of molecules whose abundance was selectively elevated in the active conditioned medium fraction. CONCLUSIONS:: Human amniotic mesenchymal stromal cell-secreted factors protect the brain after acute injury. Importantly, a fraction rich in metabolites, and containing neither proteic nor ribonucleic molecules was protective. This study indicates the profiling of protective factors that could be useful in cell-free therapeutic approaches for acute brain injury.

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