Dataset Information

A Rat Model of Radiation Vasculitis for the Study of Mesenchymal Stem Cell-Based Therapy.

ABSTRACT: Radiation vasculitis is one of the most common detrimental effects of radiotherapy for malignant tumors. This is developed at the vasculature of adjacent organs. Animal experiments have showed that transplantation of mesenchymal stem cells (MSCs) restores vascular function after irradiation. But the population of MSCs being engrafted into irradiated vessels is too low in the conventional models to make assessment of therapeutic effect difficult. This is presumably because circulating MSCs are dispersed in adjacent tissues being irradiated simultaneously. Based on the assumption, a rat model, namely, RT (radiation) plus TX (transplantation), was established to promote MSC homing by sequestering irradiated vessels. In this model, a 1.5 cm long segment of rat abdominal aorta was irradiated by 160kV X-ray at a single dose of 35Gy before being procured and grafted to the healthy counterpart. F344 inbred rats served as both donors and recipients to exclude the possibility of immune rejection. A lead shield was used to confine X-ray delivery to a 3 cm×3 cm square-shaped field covering central abdominal region. The abdominal viscera especially small bowel and colon were protected from irradiation by being pushed off the central abdominal cavity. Typical radiation-induced vasculopathy was present on the 90^th day after irradiation. The recruitment of intravenously injected MSCs to irradiated aorta was significantly improved by using the RT-plus-TX model as compared to the model with irradiation only. Generally, the RT-plus-Tx model promotes MSC recruitment to irradiated aorta by separating irradiated vascular segment from adjacent tissue. Thus, the model is preferred in the study of MSC-based therapy for radiation vasculitis when the evaluation of MSC homing is demanding.

SUBMITTER: Zhang J

PROVIDER: S-EPMC6431386 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A Rat Model of Radiation Vasculitis for the Study of Mesenchymal Stem Cell-Based Therapy.

Zhang Jian J Tao Xuan X Sun Mingyang M Ying Rongchao R Su Wenjie W Wei Wei W Meng Xiaohu X

BioMed research international 20190306

Radiation vasculitis is one of the most common detrimental effects of radiotherapy for malignant tumors. This is developed at the vasculature of adjacent organs. Animal experiments have showed that transplantation of mesenchymal stem cells (MSCs) restores vascular function after irradiation. But the population of MSCs being engrafted into irradiated vessels is too low in the conventional models to make assessment of therapeutic effect difficult. This is presumably because circulating MSCs are di ...[more]

PMID: 30956979

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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.

Project description:Periurethral human mesenchymal stem cell (hMSC) injections are associated with functional improvement in animal models of postpartum stress urinary incontinence (SUI). However, limited data exist on the role of hMSCs in modulating gene expression in tissue repair after urethral injury. To this end, we quantified temporal gene expression modulation in hMSCs, and in injured rat urethral tissue, using RNA-seq in an animal model of SUI, over a 3-day period following urethral injury, and local hMSC injection. We injected PKH fluorescent-labeled hMSC into the periurethral space of rats following a 4 h vaginal distention (VD) (three rats per time point). Control rats underwent VD injury only, and all animals were euthanized at 12, 24, 36, 72 h postinjury. Rat urethral and vaginal tissues were frozen and sectioned. Fluorescent labeled hMSCs were distinguished from adjacent, unlabeled rat urethral tissue. RNA was prepared from hMSCs and urethral tissue obtained by laser dissection of frozen tissue sections and sequenced on an Illumina HiSeq 2500. Differentially expressed genes (DEGs) over 72 h were evaluated using a two-group t-test (p < 0.05). Our transcriptional analyses identified candidate genes involved in tissue injury that were broadly sorted by injury and exposure to hMSC throughout the first 72 h of acute phase of injury. DEGs in treated urethra, compared with untreated urethra, were functionally associated with tissue repair, angiogenesis, neurogenesis, and oxidative stress suppression. DEGs included a variety of cytokines, extracellular matrix stabilization and regeneration genes, cytokine signaling modification, cell cycle regulation, muscle differentiation, and stabilization. Moreover, our results revealed DEG changes in hMSCs (PKH-labeled) harvested from injured urethra. The expressions are related to DNA damage repair, transcription activation, stem cell regulation, cell survival, apoptosis, self-renewal, cell proliferation, migration, and injury response. Impact statement Stress urinary incontinence (SUI) affects nearly half of women over 40, resulting in reduced quality of life and increased health care cost. Development of SUI is multifactorial and strongly associated with vaginal delivery. While stem cell therapy in animal models of SUI and limited preliminary clinical trials demonstrate functional improvement of SUI, the role of stem cell therapy in modulating tissue repair is unclear impeding advanced clinical trials. Our work provides a new understanding of the transcriptional mechanisms with which human mesenchymal stem cells improve acute injury repair thus guiding the development of cell-based therapies for women with nonacute established SUI.

Dataset Information

A Rat Model of Radiation Vasculitis for the Study of Mesenchymal Stem Cell-Based Therapy.

Publications

A Rat Model of Radiation Vasculitis for the Study of Mesenchymal Stem Cell-Based Therapy.

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