Proteomic analysis of human mesenchymal stromal cell secretomes: a systematic comparison of the angiogenic potential

Kehl, Debora; Generali, Melanie; Mallone, Anna; Heller, Manfred; Uldry, Anne-Christine; Cheng, Phil F.; Gantenbein, Benjamin; Hoerstrup, Simon P.; Weber, Benedikt

doi:10.1038/s41536-019-0070-y

Cited by 165 publications

(138 citation statements)

References 43 publications

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“…This is in line with a previous study on cancer cells that clarified the increase in cell migration by delivery of some ECM molecules through exosomes [32]. In addition, the secretome from MSCs showed a positive effect on angiogenesis and chemotaxis of leukocytes [33]. However, further work is needed to characterize the protein and miRNA profile of the exosomes from the pulp to better understand the underlying mechanisms.…”

Section: Discussionsupporting

confidence: 85%

Pulp-Derived Exosomes in a Fibrin-Based Regenerative Root Filling Material

Ivica

Ghayor

Zehnder

et al. 2020

JCM

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Regenerative endodontics has been described as a paradigm shift in dentistry, despite its current limitation to immature teeth and reparative rather than regenerative outcomes. Cell-free treatments are favored because of regulatory issues. However, the recruitment of host-derived stem cells to the desired site remains challenging. We investigated whether dental pulp-derived exosomes, which are extracellular vesicles that contain proteins, lipids, RNA, and DNA and thus mirror their parental cells, may be used for this purpose. The use of exosomes may present appreciable advantages over the direct use of transplanted stem cells due to a higher safety profile, easier isolation, preservation, and handling. Here we harvested exosomes from a cultured third-molar pulp cell and assessed them by transmission electron microscopy and Western blotting. Human mesenchymal stem cells (MSCs) were exposed to these exosomes to assess exosome uptake, cell migration, and proliferation. In addition, a fibrin gel (i.e., a diluted fibrin sealant), was assessed as a delivery system for the exosomes. Our results show that exosomes attracted MSCs, and the fibrin gel enhanced their effect. Moreover, exosomes improved the proliferation of MSCs. Therefore, we propose that pulp-derived exosomes in combination with a fibrin gel could be a powerful combination for clinical translation towards improved cell-free regenerative endodontics and thus represent a new way to fill dental hard tissues.

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Section: Discussionsupporting

confidence: 85%

Pulp-Derived Exosomes in a Fibrin-Based Regenerative Root Filling Material

Ivica

Ghayor

Zehnder

et al. 2020

JCM

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“…Despite UCMSCs having similar PDTs between conditions, hypoxia is still worth exploring as animal studies have shown that UCMSCs, grown in hypoxia, have a higher angiogenic potential in the treatment of mouse hindlimb ischaemia [33,34] and rat spinal cord injury in comparison to UCMSCs grown in normoxia [35]. Indeed, the pro-angiogenic protein VEGF-A [36][37][38], was expressed in all conditions but upregulated in hypoxic/primed EV samples. VEGF-A is a well-documented hypoxic-induced response [39], there might be other hypoxic related changes in the EVs that weren't detected in this array; an array covering a broader repertoire of proteins might have identified more hypoxic-mediated changes.…”

Section: Discussionmentioning

confidence: 99%

Pro-Inflammatory Priming of Umbilical Cord Mesenchymal Stromal Cells Alters the Protein Cargo of Their Extracellular Vesicles

Hyland

Mennan

Wilson

et al. 2020

Cells

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Umbilical cord mesenchymal stromal cells (UCMSCs) have shown an ability to modulate the immune system through the secretion of paracrine mediators, such as extracellular vesicles (EVs). However, the culture conditions that UCMSCs are grown in can alter their secretome and thereby affect their immunomodulatory potential. UCMSCs are commonly cultured at 21% O 2 in vitro, but recent research is exploring their growth at lower oxygen conditions to emulate circulating oxygen levels in vivo. Additionally, a pro-inflammatory culture environment is known to enhance UCMSC anti-inflammatory potential. Therefore, this paper examined EVs from UCMSCs grown in normal oxygen (21% O 2 ), low oxygen (5% O 2 ) and pro-inflammatory conditions to see the impact of culture conditions on the EV profile. EVs were isolated from UCMSC conditioned media and characterised based on size, morphology and surface marker expression. EV protein cargo was analysed using a proximity-based extension assay. Results showed that EVs had a similar size and morphology. Differences were found in EV protein cargo, with pro-inflammatory primed EVs showing an increase in proteins associated with chemotaxis and angiogenesis. This showed that the UCMSC culture environment could alter the EV protein profile and might have downstream implications for their functions in immunomodulation.

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“…Our recent work has demonstrated the secretome of BM‐MSCs can act as a biotherapeutic agent to stimulate murine pancreatic islet regeneration in vivo independent of cell transplantation . It remains to be determined whether a functionally “therapeutic” secretome is uniform across MSCs from different tissue sources, as the protein composition of an MSC‐generated secretome appears tissue‐specific . The advancement of human islet transplantation has generated cadaveric pancreatic tissue distribution centers, such as Integrated Islet Distribution Program (IIDP), that provide a reliable source of demographically diverse pancreatic tissue that may be used to establish MSC colonies from a previously unattainable source.…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Vimentinhigh/Nestinhigh proteome and tissue regenerative secretome generated by human pancreas-derived mesenchymal stromal cells

Cooper

Sherman

Bell³

et al. 2020

Stem Cells

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Multipotent/mesenchymal stromal cells (MSCs) exist within a variety of postnatal tissues; however, global proteomic analyses comparing tissue-specific MSC are limited. Using human bone marrow (BM)-derived MSCs as a gold standard, we used label-free mass spectrometry and functional assays to characterize the proteome, secretome, and corresponding function of human pancreas-derived MSCs (Panc-MSCs) with a classical phenotype (CD90+/CD73+/CD105+/CD45−/CD31−). Both MSC subtypes expressed mesenchymal markers vimentin, α-SMA, and STRO-1; however, expression of nestin was increased in Panc-MSCs. Accordingly, these Vimentin high /Nestin high cells were isolated from fresh human pancreatic islet and non-islet tissues. Next, we identified expression of >60 CD markers shared between Panc-MSCs and BM-MSCs, including validated expression of CD14. An additional 19 CD markers were differentially expressed, including reduced pericyte-marker CD146 expression on Panc-MSCs. Panc-MSCs also showed reduced expression of proteins involved in lipid and retinoid metabolism. Accordingly, Panc-MSCs showed restricted responses to adipogenic stimuli in vitro, although both MSC types demonstrated trilineage differentiation. In contrast, Panc-MSCs demonstrated accelerated growth kinetics and competency to proneurogenic stimuli in vitro. The secretome of Panc-MSCs was highly enriched for proteins associated with vascular development, wound healing and chemotaxis. Similar to BM-MSCs, Panc-MSCs conditioned media augmented endothelial cell survival, proliferation, and tubule formation in vitro. Importantly, the secretome of both MSC types was capable of stimulating chemotactic infiltration of murine endothelial cells in vivo and reduced hyperglycemia in STZ-treated mice following intrapancreatic injection. Overall, this study provides foundational knowledge to develop Panc-MSCs as a unique MSC subtype with functional properties beneficial in regenerative medicine for diabetes and vascular disease. K E Y W O R D S adipogenesis, multipotent stromal cells, nestin, pancreas, proteomics, regenerative medicine, secretome

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Proteomic analysis of human mesenchymal stromal cell secretomes: a systematic comparison of the angiogenic potential

Cited by 165 publications

References 43 publications

Pulp-Derived Exosomes in a Fibrin-Based Regenerative Root Filling Material

Pulp-Derived Exosomes in a Fibrin-Based Regenerative Root Filling Material

Pro-Inflammatory Priming of Umbilical Cord Mesenchymal Stromal Cells Alters the Protein Cargo of Their Extracellular Vesicles

Characterization of a Vimentinhigh/Nestinhigh proteome and tissue regenerative secretome generated by human pancreas-derived mesenchymal stromal cells

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