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Pre-exposure of human adipose mesenchymal stem cells to soluble factors enhances their homing to brain cancer.

ABSTRACT: Recent research advances have established mesenchymal stem cells (MSCs) as a promising vehicle for therapeutic delivery. Their intrinsic tropism for brain injury and brain tumors, their lack of immunogenicity, and their ability to breach the blood-brain barrier make these cells an attractive potential treatment of brain disorders, including brain cancer. Despite these advantages, the efficiency of MSC homing to the brain has been limited in commonly used protocols, hindering the feasibility of such therapies. In the present study, we report a reproducible, comprehensive, cell culture-based approach to enhance human adipose-derived MSC (hAMSC) engraftment to brain tumors. We used micro- and nanotechnological tools to systematically model several steps in the putative homing process. By pre-exposing hAMSCs to glioma-conditioned media and the extracellular matrix proteins fibronectin and laminin, we achieved significant enhancements of the individual homing steps in vitro. This homing was confirmed in an in vivo rodent model of brain cancer. This comprehensive, cell-conditioning approach provides a novel method to enhance stem cell homing to gliomas and, potentially, other neurological disorders.

SUBMITTER: Smith CL

PROVIDER: S-EPMC4339851 | biostudies-other | 2015 Mar

REPOSITORIES: biostudies-other

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Pre-exposure of human adipose mesenchymal stem cells to soluble factors enhances their homing to brain cancer.

Smith Chris L CL Chaichana Kaisorn L KL Lee Young M YM Lin Benjamin B Stanko Kevin M KM O'Donnell Thomas T Gupta Saksham S Shah Sagar R SR Wang Joanne J Wijesekera Olindi O Delannoy Michael M Levchenko Andre A Quiñones-Hinojosa Alfredo A

Stem cells translational medicine 20150202 3

Recent research advances have established mesenchymal stem cells (MSCs) as a promising vehicle for therapeutic delivery. Their intrinsic tropism for brain injury and brain tumors, their lack of immunogenicity, and their ability to breach the blood-brain barrier make these cells an attractive potential treatment of brain disorders, including brain cancer. Despite these advantages, the efficiency of MSC homing to the brain has been limited in commonly used protocols, hindering the feasibility of s ...[more]

PMID: 25646527

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Project description:Tissue regeneration or healing both require efficient vascularization within a tissue-damaged area. Based on this concept, a remarkable number of strategies, aimed at developing new tools to support re-vascularization of damaged tissue have emerged. Among the strategies proposed, the use of pro-angiogenic soluble factors, as a cell-free tool, appears as a promising approach, able to overcome the issues concerning the direct use of cells for regenerative medicine therapy. Here, we compared the effectiveness of adipose mesenchymal stem cells (ASCs), use as cell suspension, ASC protein extract or ASC-conditioned-medium (i.e., soluble factors), combined with collagenic scaffold, in supporting in vivo angiogenesis. We also tested the capability of hypoxia in increasing the efficiency of ASC to promote angiogenesis, via soluble factors, both in vivo and in vitro. In vivo studies were performed using the Integra® Flowable Wound Matrix, and the Ultimatrix in sponge assay. Flow cytometry was used to characterize the scaffold- and sponge-infiltrating cells. Real-time PCR was used to evaluate the expression of pro-angiogenic factors by stimulating Human Umbilical-Vein Endothelial Cells with ASC-conditioned media, obtained in hypoxic and normoxic conditions. We found that, in vivo, ACS-conditioned media can support angiogenesis similar to ASCs and ASC protein extract. Also, we observed that hypoxia increases the pro-angiogenic activities of ASC-conditioned media, compared to normoxia, by generating a secretome enriched in pro-angiogenic soluble factors, with bFGF, Adiponectine, ENA78, GRO, GRO-a, and ICAM1-3, as most regulated factors. Finally, ASC-conditioned media, produced in hypoxic condition, induce the expression of pro-angiogenic molecules in HUVECs. Our results provide evidence that ASC-conditioned-medium can be proposed as a cell-free preparation able to support angiogenesis, thus providing a relevant tool to overcome the issues and restrictions associated with the use of cells.

Project description:Purpose: Iron oxide based magnetic nanoparticles (MNP) are versatile tools in biology and medicine. Adipose derived mesenchymal stem cells (ADSC) and Wharton Jelly mesenchymal stem cells (WJMSC) are currently tested in different strategies for regenerative regenerative medicine (RM) purposes. Their superiority compared to other mesenchymal stem cell consists in larger availability, and superior proliferative and differentiation potential. Magnetic field (MF) exposure of MNP-loaded ADSC has been proposed as a method to deliver mechanical stimulation for increasing conversion to musculoskeletal lineages. In this study, we investigated comparatively chondrogenic conversion of ADSC-MNP and WJMSC with or without MF exposure in order to identify the most appropriate cell source and differentiation protocol for future cartilage engineering strategies. Methods: Human primary ADSC and WJMSC from various donors were loaded with proprietary uncoated MNP. The in vitro effect on proliferation and cellular senescence (beta galactosidase assay) in long term culture was assessed. In vitro chondrogenic differentiation in pellet culture system, with or without MF exposure, was assessed using pellet histology (Safranin O staining) as well as quantitative evaluation of glycosaminoglycan (GAG) deposition per cell. Results: ADSC-MNP complexes displayed superior proliferative capability and decreased senescence after long term (28 days) culture in vitro compared to non-loaded ADSC and to WJMSC-MNP. Significant increase in chondrogenesis conversion in terms of GAG/cell ratio could be observed in ADSC-MNP. MF exposure increased glycosaminoglycan deposition in MNP-loaded ADSC, but not in WJMSC. Conclusion: ADSC-MNP display decreased cellular senescence and superior chondrogenic capability in vitro compared to non-loaded cells as well as to WJMSC-MNP. MF exposure further increases ADSC-MNP chondrogenesis in ADSC, but not in WJMSC. Loading ADSC with MNP can derive a successful procedure for obtaining improved chondrogenesis in ADSC. Further in vivo studies are needed to confirm the utility of ADSC-MNP complexes for cartilage engineering.

Dataset Information

Pre-exposure of human adipose mesenchymal stem cells to soluble factors enhances their homing to brain cancer.

Publications

Pre-exposure of human adipose mesenchymal stem cells to soluble factors enhances their homing to brain cancer.

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