Cellular Aging Secretes: a Comparison of Bone-Marrow-Derived and Induced Mesenchymal Stem Cells and Their Secretome Over Long-Term Culture

Marote, Ana; Santos, Diogo; Mendes-Pinheiro, Bárbara; Serre-Miranda, Cláudia; Anjo, Sandra I.; Vieira, Joana; Ferreira-Antunes, F.; Correia, J. H.; Borges-Pereira, Caroline; Pinho, Andreia G.; Campos, Jonas; Manadas, Bruno; Teixeira, Manuel R.; Correia-Neves, Margarida; Pinto, Luís; Costa, Pedro M. F. J.; Roybon, Laurent; Salgado, António J.

doi:10.1007/s12015-022-10453-6

Cited by 9 publications

(13 citation statements)

References 65 publications

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“…Other studies testing the effect of ageing on MSC CM all utilised the in vitro models of ageing through long-term culture, that are characterised by decreased cell proliferation capacity. 33–37 Although replicative senescence reflects only one of the aspects of cellular ageing, increasing concentrations of MCP-1 in CM was observed both in MSCs from older horses and late passage human BMSCs. 33–35 In vitro studies showed that the abundance of most CM proteins remains unchanged with progressive cell passaging, 36,37 however, proteins upregulated in late passage BMSCs had a senescence-inducing effect on early passage cells.…”

Section: Discussionmentioning

confidence: 99%

“…33–37 Although replicative senescence reflects only one of the aspects of cellular ageing, increasing concentrations of MCP-1 in CM was observed both in MSCs from older horses and late passage human BMSCs. 33–35 In vitro studies showed that the abundance of most CM proteins remains unchanged with progressive cell passaging, 36,37 however, proteins upregulated in late passage BMSCs had a senescence-inducing effect on early passage cells. 36 Our results likewise suggests that the abundance of most proteins in equine MSC CM is unaffected by donor age, yet the age-related decrease in CTHRC1, LOX may have functional implications, due to the role of these proteins in regulation of ECM remodelling.…”

Section: Discussionmentioning

confidence: 99%

“…Untargeted proteomics was previously used to investigate differences in composition of conditioned media (CM) from MSCs isolated from various tissue sources [30][31][32][33] and from different passages of a longterm cell culture, serving as an in vitro model of ageing. [33][34][35][36][37] In vitro ageing does not reflect the complexity of chronological ageing, and these two processes were previously shown to have a different impact on the function of rat adipose-derived MSCs. 38 Therefore, MSC data from donors of different ages is needed to fully assess the relationship between MSC ageing and secreted proteins.…”

Section: Introductionmentioning

confidence: 99%

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Mesenchymal Stromal Cell secretome is affected by tissue source, donor age and sex

Turło¹,

Hammond²,

Ramsbottom³

et al. 2023

Preprint

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Variation in Mesenchymal Stromal Cell (MSC) function depending on their origin is problematic, as it may confound clinical outcomes of MSC therapy. Current evidence suggests that the therapeutic benefits of MSCs is primarily attributed to secretion of various biologically active factors (secretome). However, the effect of donor characteristics on the MSC secretome composition remains largely unknown. Here, we examined the influence of donor age, sex and tissue source, on the protein profile of the equine MSC secretome. Initially, we used dynamic metabolic labelling with stable isotopes combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify secreted proteins in MSC conditioned media (CM). Seventy proteins were classified as classically-secreted based on the rate of isotope label incorporation into newly synthesised proteins released into the extracellular space. Next, we analysed CM of bone marrow- (n = 14) and adipose-derived MSCs (n = 16) with label-free LC-MS/MS proteomics. Clustering analysis of 314 proteins detected across all samples identified tissue source as the main factor driving variability in MSC CM proteomes. Linear modelling applied to the subset of 70 secreted proteins identified tissue-related difference in the abundance of 23 proteins. There was an age-related decrease in the abundance of two proteins (CTHRC1, LOX), which has been validated with western blot and enzymatic activity assay. There was limited evidence of sex-related differences in protein abundance. In conclusion, this study provides evidence that tissue source and donor age contribute to heterogeneity in the protein composition of MSC secretomes which may influence the effects of MSC-based cell therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mesenchymal Stromal Cell secretome is affected by tissue source, donor age and sex

Turło¹,

Hammond²,

Ramsbottom³

et al. 2023

Preprint

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“…Human iPSCs, by Marote et al [ 42 ], were used to generate the brain organoids. iPSCs were cultured on Vitronectin XF™ (Stem Cell Technology, France) coated plates in mTeSR™1 medium (Stem Cell Technology, France), kept at 37 °C (5% CO 2 ) for 6–7 days with daily medium changes, and split using manual passage.…”

Section: Methodsmentioning

confidence: 99%

“…The Informed Consent Statement on the human samples used to derive in iPSCs, which were used in this study, are described in Ref. [ 42 ].…”

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confidence: 99%

Cerebral Malaria Model Applying Human Brain Organoids

Silva-Pedrosa

Campos

Fernandes

et al. 2023

Cells

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Neural injuries in cerebral malaria patients are a significant cause of morbidity and mortality. Nevertheless, a comprehensive research approach to study this issue is lacking, so herein we propose an in vitro system to study human cerebral malaria using cellular approaches. Our first goal was to establish a cellular system to identify the molecular alterations in human brain vasculature cells that resemble the blood–brain barrier (BBB) in cerebral malaria (CM). Through transcriptomic analysis, we characterized specific gene expression profiles in human brain microvascular endothelial cells (HBMEC) activated by the Plasmodium falciparum parasites. We also suggest potential new genes related to parasitic activation. Then, we studied its impact at brain level after Plasmodium falciparum endothelial activation to gain a deeper understanding of the physiological mechanisms underlying CM. For that, the impact of HBMEC-P. falciparum-activated secretomes was evaluated in human brain organoids. Our results support the reliability of in vitro cellular models developed to mimic CM in several aspects. These systems can be of extreme importance to investigate the factors (parasitological and host) influencing CM, contributing to a molecular understanding of pathogenesis, brain injury, and dysfunction.

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Lipid Priming of Adipose Mesenchymal Stromal Cells with Docosahexaenoic Acid: Impact on Cell Differentiation, Senescence and the Secretome Neuroregulatory Profile

Campos,

Sampaio-Marques,

Santos

et al. 2024

Tissue Eng Regen Med

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Background: Priming strategies that improve the functionality of MSCs may be required to address issues limiting successful clinical translation of MSC therapies. For conditions requiring high trophic support such as brain and spinal cord injuries, priming MSCs to produce higher levels of trophic factors may be instrumental to facilitate translation of current MSC therapies. We developed and tested a novel molecular priming paradigm using docosahexaenoic acid (DHA) to prime adipose tissue-derived mesenchymal stromal cells (ASCs) to enhance the secretome neuroregulatory potential. Methods: Comprehensive dose–response and time-course assays were carried to determine an optimal priming protocol. Secretome total protein measurements were taken in association with cell viability, density and morphometric assessments. Cell identity and differentiation capacity were studied by flow cytometry and lineage-specific markers. Cell growth was assessed by trypan-blue exclusion and senescence was probed over time using SA-β-gal, morphometry and gene expression. Secretomes were tested for their ability to support differentiation and neurite outgrowth of human neural progenitor cells (hNPCs). Neuroregulatory proteins in the secretome were identified using multiplex membrane arrays. Results: Priming with 40 µM DHA for 72 h significantly enhanced the biosynthetic capacity of ASCs, producing a secretome with higher protein levels and increased metabolic viability. DHA priming enhanced ASCs adipogenic differentiation and adapted their responses to replicative senescence induction. Furthermore, priming increased concentrations of neurotrophic factors in the secretome promoting neurite outgrowth and modulating the differentiation of hNPCs. Conclusions: These results provide proof-of-concept evidence that DHA priming is a viable strategy to improve the neuroregulatory profile of ASCs.

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Cellular Aging Secretes: a Comparison of Bone-Marrow-Derived and Induced Mesenchymal Stem Cells and Their Secretome Over Long-Term Culture

Cited by 9 publications

References 65 publications

Mesenchymal Stromal Cell secretome is affected by tissue source, donor age and sex

Mesenchymal Stromal Cell secretome is affected by tissue source, donor age and sex

Cerebral Malaria Model Applying Human Brain Organoids

Lipid Priming of Adipose Mesenchymal Stromal Cells with Docosahexaenoic Acid: Impact on Cell Differentiation, Senescence and the Secretome Neuroregulatory Profile

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