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Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2D and 3D conditions improves functional recovery in rats after traumatic brain injury.

ABSTRACT: Multipotent human bone marrow derived mesenchymal stem cells (hMSCs) improve functional outcome after experimental traumatic brain injury (TBI). The present study was designed to investigate whether systemic administration of cell-free exosomes generated from hMSCs cultured in 2-dimensional (2D) conventional conditions or in 3-dimensional (3D) collagen scaffolds promote functional recovery and neurovascular remodeling in rats after TBI. Wistar rats were subjected to TBI induced by controlled cortical impact; 24 h later tail vein injection of exosomes derived from hMSCs cultured under 2D or 3D conditions or an equal number of liposomes as a treatment control were performed. The modified Morris water maze, neurological severity score and footfault tests were employed to evaluate cognitive and sensorimotor functional recovery. Animals were sacrificed at 35 days after TBI. Histological and immunohistochemical analyses were performed for measurements of lesion volume, neurovascular remodeling (angiogenesis and neurogenesis), and neuroinflammation. Compared with liposome-treated control, exosome-treatments did not reduce lesion size but significantly improved spatial learning at 33-35 days measured by the Morris water maze test, and sensorimotor functional recovery, i.e., reduced neurological deficits and footfault frequency, observed at 14-35 days post injury (p < 0.05). Exosome treatments significantly increased the number of newborn endothelial cells in the lesion boundary zone and dentate gyrus, and significantly increased the number of newborn mature neurons in the dentate gyrus as well as reduced neuroinflammation. Exosomes derived from hMSCs cultured in 3D scaffolds provided better outcome in spatial learning than exosomes from hMSCs cultured in the 2D condition. In conclusion, hMSC-generated exosomes significantly improve functional recovery in rats after TBI, at least in part, by promoting endogenous angiogenesis and neurogenesis and reducing neuroinflammation. Thus, exosomes derived from hMSCs may be a novel cell-free therapy for TBI, and hMSC-scaffold generated exosomes may selectively enhance spatial learning.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC5311054 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2D and 3D conditions improves functional recovery in rats after traumatic brain injury.

Zhang Yanlu Y Chopp Michael M Zhang Zheng Gang ZG Katakowski Mark M Xin Hongqi H Qu Changsheng C Ali Meser M Mahmood Asim A Xiong Ye Y

Neurochemistry international 20160815

Multipotent human bone marrow derived mesenchymal stem cells (hMSCs) improve functional outcome after experimental traumatic brain injury (TBI). The present study was designed to investigate whether systemic administration of cell-free exosomes generated from hMSCs cultured in 2-dimensional (2D) conventional conditions or in 3-dimensional (3D) collagen scaffolds promote functional recovery and neurovascular remodeling in rats after TBI. Wistar rats were subjected to TBI induced by controlled cor ...[more]

PMID: 27539657

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Project description:BackgroundBombyx mori silk fibroin is a biomacromolecule that allows the assembly of scaffolds for tissue engineering and regeneration purposes due to its cellular adhesiveness, high biocompatibility and low immunogenicity. Earlier work showed that two types of 3D silk fibroin nonwovens (3D-SFnws) implanted into mouse subcutaneous tissue were promptly vascularized via undefined molecular mechanisms. The present study used nontumorigenic adult human dermal fibroblasts (HDFs) adhering to a third type of 3D-SFnws to assess whether HDFs release exosomes whose contents promote neoangiogenesis.MethodsElectron microscopy imaging and physical tests defined the features of the novel carded/hydroentangled 3D-SFnws. HDFs were cultured on 3D-SFnws and polystyrene plates in an exosome-depleted medium. DNA amounts and D-glucose consumption revealed the growth and metabolic activities of HDFs on 3D-SFnws. CD9-expressing total exosome fractions were from conditioned media of 3D-SFnws and 2D polystyrene plates HDF cultures. Angiogenic growth factors (AGFs) in equal amounts of the two groups of exosomal proteins were analysed via double-antibody arrays. A tube formation assay using human dermal microvascular endothelial cells (HDMVECs) was used to evaluate the exosomes' angiogenic power.ResultsThe novel features of the 3D-SFnws met the biomechanical requirements typical of human soft tissues. By experimental day 15, 3D-SFnws-adhering HDFs had increased 4.5-fold in numbers and metabolized 5.4-fold more D-glucose than at day 3 in vitro. Compared to polystyrene-stuck HDFs, exosomes from 3D-SFnws-adhering HDFs carried significantly higher amounts of AGFs, such as interleukin (IL)-1α, IL-4 and IL-8; angiopoietin-1 and angiopoietin-2; angiopoietin-1 receptor (or Tie-2); growth-regulated oncogene (GRO)-α, GRO-β and GRO-γ; matrix metalloproteinase-1; tissue inhibitor metalloproteinase-1; and urokinase-type plasminogen activator surface receptor, but lesser amounts of anti-angiogenic tissue inhibitor metalloproteinase-2 and pro-inflammatory monocyte chemoattractant protein-1. At concentrations from 0.62 to 10 μg/ml, the exosomes from 3D-SFnws-cultured HDFs proved their angiogenic power by inducing HDMVECs to form significant amounts of tubes in vitro.ConclusionsThe structural and mechanical properties of carded/hydroentangled 3D-SFnws proved their suitability for tissue engineering and regeneration applications. Consistent with our hypothesis, 3D-SFnws-adhering HDFs released exosomes carrying several AGFs that induced HDMVECs to promptly assemble vascular tubes in vitro. Hence, we posit that once implanted in vivo, the 3D-SFnws/HDFs interactions could promote the vascularization and repair of extended skin wounds due to burns or other noxious agents in human and veterinary clinical settings.

Project description:Background The therapeutic IgG1 anti-CD20 antibody, rituximab (RTX), has greatly improved prognosis of many B-cell malignancies. Despite its success, resistance has been reported and detailed knowledge of RTX mechanisms are lacking. Complement-dependent cytotoxicity (CDC) is one important mode of action of RTX. The aim of this study was to systematically evaluate factors influencing complement-mediated tumor cell killing by RTX. Methods Different RTX isotypes, IgG1, IgG3, IgA1 and IgA2 were evaluated and administered on four human CD20+ B-cell lymphoma cell lines, displaying diverse expression of CD20 and complement-regulatory protein CD59. Complement activation was assessed on lymphoma cells grown in 2 and 3-dimensional (3D) culture systems by trypan blue exclusion. CDC in 3D spheroids was additionally analyzed by Annexin V and propidium iodide staining by flow cytometry, and confocal imaging. Anti-CD59 antibody was used to evaluate influence of CD59 in RTX-mediated CDC responses. Statistical differences were determined by one-way ANOVA and Tukey post hoc test. Results We found that 3 out of 4 lymphomas were sensitive to RTX-mediated CDC when cultured in 2D, while 2 out of 4 when grown in 3D. RTX-IgG3 had the greatest CDC potential, followed by clinical standard RTX-IgG1 and RTX-IgA2, whereas RTX-IgA1 displayed no complement activation. Although the pattern of different RTX isotypes to induce CDC were similar in the sensitive lymphomas, the degree of cell killing differed. A greater CDC activity was seen in lymphoma cells with a higher CD20/CD59 expression ratio. These lymphomas were also sensitive to RTX when grown in 3D spheroids, although the CDC activity was substantially reduced compared to 2D cultures. Analysis of RTX-treated spheroids demonstrated apoptosis and necrosis essentially in the outer cell-layers. Neutralization of CD59 overcame resistance to RTX-mediated CDC in 2D-cultured lymphoma cells, but not in spheroids. Conclusions The results demonstrate that CDC outcome in CD20+ B-cell lymphoma is synergistically influenced by choice of RTX isotype, antigen density, tumor structure, and degree of CD59 expression. Assessment of tumor signatures, such as CD20/CD59 ratio, can be advantageous to predict CDC efficiency of RTX in vivo and may help to develop rational mAbs to raise response rates in patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09772-1.

Dataset Information

Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2D and 3D conditions improves functional recovery in rats after traumatic brain injury.

Publications

Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2D and 3D conditions improves functional recovery in rats after traumatic brain injury.

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