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7-T MRI tracking of mesenchymal stromal cells after lung injection in a rat model.

ABSTRACT: BACKGROUND:Mesenchymal stromal cells (MSCs) are able to migrate and engraft at sites of inflammation, injuries, and tumours, but little is known about their fate after local injection. The purpose of this study is to perform MSC tracking, combining in vivo 7-T magnetic resonance imaging (MRI) and histological assessment, following lung injection in a rat model. METHODS:Five lungs were injected with ferumoxide-labelled MSCs and five with perfluorocarbon-labelled MSCs and underwent 7-T MRI. MRI acquisitions were recorded immediately (T0), at 24?h (T24) and/or 48?h (T48) after injection. For each rat, labelled cells were assessed in the main organs by MRI. Target organs were harvested under sterile conditions from rats sacrificed 0, 24, or 48?h after injection and fixed for histological analysis via confocal and structured illumination microscopy. RESULTS:Ferumoxide-labelled MSCs were not detectable in the lungs, whereas they were not visible in the distant sites. Perfluorocarbon-labelled MSCs were seen in 5/5 injected lungs at T0, in 1/2 at T24, and in 1/3 at T48. The fluorine signal in the liver was seen in 3/5 at T0, in 1/2 at T24, and in 2/3 at T48. Post-mortem histology confirmed the presence of MSCs in the injected lung. CONCLUSIONS:Ferumoxide-labelled cells were not seen at distant sites; a linear decay of injected perfluorocarbon-labelled MSCs was observed at T0, T24, and T48 in the lung. In more than half of the experiments, perfluorocarbon-labelled MSCs scattering to the liver was observed, with a similar decay over time as observed in the lung.

SUBMITTER: Rizzo S

PROVIDER: S-EPMC7541802 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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7-T MRI tracking of mesenchymal stromal cells after lung injection in a rat model.

Rizzo Stefania S Padelli Francesco F Rinaldi Elena E Gioeni Daniela D Aquino Domenico D Brizzola Stefano S Acocella Fabio F Spaggiari Lorenzo L Baggi Fulvio F Bellomi Massimo M Bruzzone Maria Grazia MG Petrella Francesco F

European radiology experimental 20201008 1

<h4>Background</h4>Mesenchymal stromal cells (MSCs) are able to migrate and engraft at sites of inflammation, injuries, and tumours, but little is known about their fate after local injection. The purpose of this study is to perform MSC tracking, combining in vivo 7-T magnetic resonance imaging (MRI) and histological assessment, following lung injection in a rat model.<h4>Methods</h4>Five lungs were injected with ferumoxide-labelled MSCs and five with perfluorocarbon-labelled MSCs and underwent ...[more]

PMID: 33029694

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Project description:Cell therapy using mesenchymal stromal cells (MSCs) is being studied for its immunosuppressive effects. In organ transplantation, the amount of MSCs that accumulate in transplanted organs and other organs may differ depending on administration timing, which may impact their immunosuppressive effects. In vitro, adipose-derived mesenchymal stem cells (ADMSCs) suppress lymphocyte activation under cell-to-cell contact conditions. However, in vivo, it is controversial whether ADMSCs are more effective in accumulating in transplanted organs or in secondary lymphoid organs. Herein, we aimed to investigate whether the timing of ADMSC administration affects its immunosuppression ability in a rat lung transplantation model. In the transplantation study, rats were intramuscularly administered half the usual dose of tacrolimus (0.5 mg/kg) every 24 h after lung transplantation. ADMSCs (1 × 106) were administered via the jugular vein before (PreTx) or after (PostTx) transplantation. Cell tracking using quantum dots was performed. ADMSCs accumulated predominantly in the lung and liver; fewer ADMSCs were distributed in the grafted lung in the PreTx group than in the PostTx group. The rejection rate was remarkably low in the ADMSC-administered groups, particularly in the PostTx group. Serum tumor necrosis factor-α (TNF-α), interferon-γ, and interleukin (IL)-6 levels showed a greater tendency to decrease in the PreTx group than in the PostTx group. The proportion of regulatory T cells in the grafted lung 10 days after transplantation was higher in the PostTx group than in the PreTx group. PostTx administration suppresses rejection better than PreTx administration, possibly due to regulatory T cell induction by ADMSCs accumulated in the transplanted lungs, suggesting a mechanism different from that in heart or kidney transplantation that PreTx administration is more effective than PostTx administration. These results could help establish cell therapy using MSCs in lung transplantation.

Project description:BackgroundMesenchymal stromal cells (MSCs) from different sources possess great therapeutic potential due to their immunomodulatory properties associated with allograft tolerance. However, a crucial role in this activity resides in extracellular vesicles (EVs) and signaling molecules secreted by cells. This study aimed to evaluate the immunomodulatory properties of donor and recipient MSCs isolated from adipose tissue (AD) or bone marrow (BM) and their EVs on kidney outcome in a rat kidney transplant model.MethodsThe heterotopic-kidney-transplant Fisher-to-Lewis rat model (F-L) was performed to study mixed cellular and humoral rejection. After kidney transplantation, Lewis recipients were assigned to 10 groups; two control groups; four groups received autologous MSCs (either AD- or BM- MSC) or EVs (derived from both cell types); and four groups received donor-derived MSCs or EVs. AD and BM-EVs were purified by ultracentrifugation. Autologous cell therapies were administered three times intravenously; immediately after kidney transplantation, 4 and 8 weeks, whereas donor-derived cell therapies were administered once intravenously immediately after transplantation. Survival and renal function were monitored. Twelve weeks after kidney transplantation grafts were harvested, infiltrating lymphocytes were analyzed by flow cytometry and histological lesions were characterized.ResultsAutologous AD- and BM-MSCs, but not their EVs, prolonged graft and recipient survival in a rat model of kidney rejection. Autologous AD- and BM-MSCs significantly improved renal function during the first 4 weeks after transplantation. The amelioration of graft function could be associated with an improvement in tubular damage, as well as in T, and NK cell infiltration. On the other side, the application of donor-derived AD-MSC was harmful, and all rats died before the end of the protocol. AD-EVs did not accelerate the rejection. Contrary to autologous MSCs results, the single dose of donor-derived BM-MSCs is not enough to ameliorate kidney graft damage.ConclusionEVs treatments did not exert any benefit in our experimental settings. In the autologous setting, BM-MSCs prompted as a potentially promising therapy to improve kidney graft outcomes in rats with chronic mixed rejection. In the donor-derived setting, AD-MSC accelerated progression to end-stage kidney disease. Further experiments are required to adjust timing and dose for better long-term outcomes.

Project description:The secretome of mesenchymal stromal cells (MSCs) is enriched for biotherapeutic effectors contained within and independent of extracellular vesicles (EVs) that may support tissue regeneration as an injectable agent. We have demonstrated that the intrapancreatic injection of concentrated conditioned media (CM) produced by bone marrow MSC supports islet regeneration and restored glycemic control in hyperglycemic mice, ultimately providing a platform to elucidate components of the MSC secretome. Herein, we extend these findings using human pancreas-derived MSC (Panc-MSC) as "biofactories" to enrich for tissue regenerative stimuli housed within distinct compartments of the secretome. Specifically, we utilized 100 kDa ultrafiltration as a simple method to debulk protein mass and to enrich for EVs while concentrating the MSC secretome into an injectable volume for preclinical assessments in murine models of blood vessel and islet regeneration. EV enrichment (EV+) was validated using nanoscale flow cytometry and atomic force microscopy, in addition to the detection of classical EV markers CD9, CD81, and CD63 using label-free mass spectrometry. EV+ CM was predominately enriched with mediators of wound healing and epithelial-to-mesenchymal transition that supported functional regeneration in mesenchymal and nonmesenchymal tissues. For example, EV+ CM supported human microvascular endothelial cell tubule formation in vitro and enhanced the recovery of blood perfusion following intramuscular injection in nonobese diabetic/severe combined immunodeficiency mice with unilateral hind limb ischemia. Furthermore, EV+ CM increased islet number and β cell mass, elevated circulating insulin, and improved glycemic control following intrapancreatic injection in streptozotocin-treated mice. Collectively, this study provides foundational evidence that Panc-MSC, readily propagated from the subculture of human islets, may be utilized for regenerative medicine applications.

Project description:OBJECTIVE:Interstitial cystitis (IC) is a chronic intractable disease. Recently, the potential application of stem cell (SC) therapy was suggested for IC management. This study aimed to establish an optimal SC source and verify the efficacy and safety of SC injection therapy in an IC rat model. DESIGN:After IC animal model induction, urine-derived stem cells (USCs), adipose tissue-derived stem cells (ADSCs), bone marrow-derived stem cells (BMSCs) and amniotic fluid-derived stem cells (AFSCs) were injected into the bladder submucosa. The following parameters were analysed: 1) functional improvement of bladder via cystometry, 2) histological changes and 3) inflammatory gene expression and regenerative potential of damaged bladder tissues. Additionally, an optimal method for SC introduction in terms of effective bladder regeneration was analysed. RESULTS:Intercontraction interval was significantly increased and inflammatory reactions and fibrotic changes were decreased in all of the SC-injected groups than in the control group. PCR analysis revealed that inflammatory gene expression significantly decreased in the USC-treated group than in the other groups. To confirm the optimal SC injection route in the IC rat model, group was divided according to the following criteria: 1) direction of SC injection into the bladder submucosa, 2) injection via tail vein, 3) transurethral instillation. In each analysis, the groups in which SCs were injected into the bladder submucosa showed significantly longer intercontraction interval, better morphologic regeneration and inhibition of bladder inflammatory reaction compared with the other groups. CONCLUSION:Regardless of the cell source, human tissue-derived mesenchymal SCs regenerated damaged bladder tissue, promoted functional recovery and inhibited inflammatory cell accumulation in an IC rat model; particularly, USC had the highest inhibitory effect on inflammation. Additionally, direct USC injection into the bladder submucosa was expected to have the best therapeutic effect, which will be an important factor for clinical applications in the future.

Dataset Information

7-T MRI tracking of mesenchymal stromal cells after lung injection in a rat model.

Publications

7-T MRI tracking of mesenchymal stromal cells after lung injection in a rat model.

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