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Repeated injections of human umbilical cord blood-derived mesenchymal stem cells significantly promotes functional recovery in rabbits with spinal cord injury of two noncontinuous segments.

ABSTRACT: BACKGROUND:Spinal cord injuries (SCIs) are sustained by an increasing number of patients each year worldwide. The treatment of SCIs has long been a hard nut to crack for doctors around the world. Mesenchymal stem cells (MSCs) have shown benefits for the repair of SCI and recovery of function. Our present study aims to investigate the effects of intravenously infused human umbilical cord blood-derived MSCs (hUCB-MSCs) on functional recovery after subacute spinal cord compression injury of two noncontinuous segments. In addition, we compared the effects of single infusion and repeated intravenous (i.v.) injections on the recovery of spinal cord function. METHODS:A total of 43 adult rabbits were randomly divided into four groups: control, single injection (SI), repeated injection at a 3-day (3RI) or repeated injection at a 7-day interval (7RI) groups. Non-immunosuppressed rabbits in the transplantation groups were infused with either a single complete dose or three divided doses of 2?×?106 hUCB-MSCs (3-day or 7-day intervals) on the first day post decompression. Behavioural scores and somatosensory evoked potentials (SEPs) were used to evaluate hindlimb functional recovery. The survival and differentiation of the transplanted human cells and the activation of the host glial and inflammatory reaction in the injured spinal cord were studied by immunohistochemical staining. RESULTS:Our results showed that hUCB-MSCs survived, proliferated, and primarily differentiated into oligodendrocytes in the injured area. Treatment with hUCB-MSCs reduced the extent of astrocytic activation, increased axonal preservation, potentially promoted axonal regeneration, decreased the number of Iba-1+ and TUNEL+ cells, increased the amplitude and decreased the onset latency of SEPs and significantly promoted functional improvement. However, these effects were more pronounced in the 3RI group compared with the SI and 7RI groups. CONCLUSIONS:Our results suggest that treatment with i.v. injected hUCB-MSCs after subacute spinal cord compression injury of two noncontinuous segments can promote functional recovery through the differentiation of hUCB-MSCs into specific cell types and the enhancement of anti-inflammatory, anti-astrogliosis, anti-apoptotic and axonal preservation effects. Furthermore, the recovery was more pronounced in the rabbits repeatedly injected with cells at 3-day intervals. The results of this study may provide a novel and useful treatment strategy for the transplantation treatment of SCI.

SUBMITTER: Yang C

PROVIDER: S-EPMC5948759 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Repeated injections of human umbilical cord blood-derived mesenchymal stem cells significantly promotes functional recovery in rabbits with spinal cord injury of two noncontinuous segments.

Yang Chaohua C Wang Gaoju G Ma Fenfen F Yu Baoqing B Chen Fancheng F Yang Jin J Feng Jianjun J Wang Qing Q

Stem cell research & therapy 20180511 1

<h4>Background</h4>Spinal cord injuries (SCIs) are sustained by an increasing number of patients each year worldwide. The treatment of SCIs has long been a hard nut to crack for doctors around the world. Mesenchymal stem cells (MSCs) have shown benefits for the repair of SCI and recovery of function. Our present study aims to investigate the effects of intravenously infused human umbilical cord blood-derived MSCs (hUCB-MSCs) on functional recovery after subacute spinal cord compression injury of ...[more]

PMID: 29751769

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Project description:Currently, there is no effective strategy to promote functional recovery after a spinal cord injury. Collagen scaffolds can not only provide support and guidance for axonal regeneration, but can also serve as a bridge for nerve regeneration at the injury site. They can additionally be used as carriers to retain mesenchymal stem cells at the injury site to enhance their effectiveness. Hence, we hypothesized that transplanting human umbilical cord-mesenchymal stem cells on collagen scaffolds would enhance healing following acute complete spinal cord injury. Here, we test this hypothesis through animal studies and a phase I clinical trial. (1) Animal experiments: Models of completely transected spinal cord injury were established in rats and canines by microsurgery. Mesenchymal stem cells derived from neonatal umbilical cord tissue were adsorbed onto collagen scaffolds and surgically implanted at the injury site in rats and canines; the animals were observed after 1 week-6 months. The transplantation resulted in increased motor scores, enhanced amplitude and shortened latency of the motor evoked potential, and reduced injury area as measured by magnetic resonance imaging. (2) Phase I clinical trial: Forty patients with acute complete cervical injuries were enrolled at the Characteristic Medical Center of Chinese People's Armed Police Force and divided into two groups. The treatment group (n = 20) received collagen scaffolds loaded with mesenchymal stem cells derived from neonatal umbilical cord tissues; the control group (n = 20) did not receive the stem-cell loaded collagen implant. All patients were followed for 12 months. In the treatment group, the American Spinal Injury Association scores and activities of daily life scores were increased, bowel and urinary functions were recovered, and residual urine volume was reduced compared with the pre-treatment baseline. Furthermore, magnetic resonance imaging showed that new nerve fiber connections were formed, and diffusion tensor imaging showed that electrophysiological activity was recovered after the treatment. No serious complication was observed during follow-up. In contrast, the neurological functions of the patients in the control group were not improved over the follow-up period. The above data preliminarily demonstrate that the transplantation of human umbilical cord-mesenchymal stem cells on a collagen scaffold can promote the recovery of neurological function after acute spinal cord injury. In the future, these results need to be confirmed in a multicenter, randomized controlled clinical trial with a larger sample size. The clinical trial was approved by the Ethics Committee of the Characteristic Medical Center of Chinese People's Armed Police Force on February 3, 2016 (approval No. PJHEC-2016-A8). All animal experiments were approved by the Ethics Committee of the Characteristic Medical Center of Chinese People's Armed Police Force on May 20, 2015 (approval No. PJHEC-2015-D5).

Project description:BackgroundSpinal cord injury (SCI) is an inflammatory condition, and excessive adenosine triphosphate (ATP) is released into the extracellular space, which can be catabolized into adenosine by CD73. Extracellular vesicles have been designed as nano drug carriers in many diseases. However, their impacts on delivery of CD73 after SCI are not yet known. We aimed to construct CD73 modified extracellular vesicles and explore the anti-inflammatory effects after SCI.MethodsCD73 engineered extracellular vesicles (CD73+ hucMSC-EVs) were firstly established, which were derived from human umbilical cord mesenchymal stem cells (hucMSCs) transduced by lentiviral vectors to upregulate the expression of CD73. Effects of CD73+ hucMSC-EVs on hydrolyzing ATP into adenosine were detected. The polarization of M2/M1 was verified by immunofluorescence. Furthermore, A2aR and A2bR inhibitors and A2bR knockdown cells were used to investigate the activated adenosine receptor. Biomarkers of microglia and levels of cAMP/PKA were also detected. Repetitively in vivo study, morphology staining, flow cytometry, cytokine analysis, and ELISA assay, were also applied for verifications.ResultsCD73+ hucMSC-EVs reduced concentration of ATP and promoted the level of adenosine. In vitro experiments, CD73+ hucMSC-EVs increased macrophages/microglia M2:M1 polarization, activated adenosine 2b receptor (A2bR), and then promoted cAMP/PKA signaling pathway. In mice using model of thoracic spinal cord contusion injury, CD73+ hucMSC-EVs improved the functional recovery after SCI through decreasing the content of ATP in cerebrospinal fluid and improving the polarization from M1 to M2 phenotype. Thus, the cascaded pro-inflammatory cytokines were downregulated, such as TNF-α, IL-1β, and IL-6, while the anti-inflammatory cytokines were upregulated, such as IL-10 and IL-4.ConclusionsCD73+ hucMSC-EVs ameliorated inflammation after spinal cord injury by reducing extracellular ATP, promoting A2bR/cAMP/PKA pathway and M2/M1 polarization. CD73+ hucMSC-EVs might be promising nano drugs for clinical application in SCI therapy.

Project description:The endometrium plays a critical role in embryo implantation and pregnancy, and a thin uterus is recognized as a key factor in embryo implantation failure. Umbilical cord mesenchymal stem cells (UC-MSCs) have attracted interest for the repair of intrauterine adhesions. The current study investigated the repair of thin endometrium in rats using the UC-MSCs and the mechanisms involved. Rats were injected with 95% ethanol to establish a model of thin endometrium. The rats were randomly divided into normal, sham, model, and UC-MSCs groups. Endometrial morphological alterations were observed by hematoxylin-eosin staining and Masson staining, and functional restoration was assessed by testing embryo implantation. The interaction between UC-MSCs and rat endometrial stromal cells (ESCs) was evaluated using a transwell 3D model and immunocytochemistry. Microarray mRNA and miRNA platforms were used for miRNA-mRNA expression profiling. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses were performed to identify the biological processes, molecular functions, cellular components, and pathways of endometrial injury and UC-MSCs transplantation repair and real-time quantitative reverse transcription PCR (qRT-PCR) was performed to further identify the expression changes of key molecules in the pathways. Endometrium thickness, number of glands, and the embryo implantation numbers were improved, and the degree of fibrosis was significantly alleviated by UC-MSCs treatment in the rat model of thin endometrium. In vitro cell experiments showed that UC-MSCs migrated to injured ESCs and enhanced their proliferation. miRNA microarray chip results showed that expression of 45 miRNAs was downregulated in the injured endometrium and upregulated after UC-MSCs transplantation. Likewise, expression of 39 miRNAs was upregulated in the injured endometrium and downregulated after UC-MSCs transplantation. The miRNA-mRNA interactions showed the changes in the miRNA and mRNA network during the processes of endometrial injury and repair. GO and KEGG analyses showed that the process of endometrial injury was mainly attributed to the decomposition of the extracellular matrix (ECM), protein degradation and absorption, and accompanying inflammation. The process of UC-MSCs transplantation and repair were accompanied by the reconstruction of the ECM, regulation of chemokines and inflammation, and cell proliferation and apoptosis. The key molecules involved in ECM-receptor interaction pathways were further verified by qRT-PCR. Itga1 and Thbs expression decreased in the model group and increased by UC-MSCs transplantation, while Laminin and Collagen expression increased in both the model group and MSCs group, with greater expression observed in the latter. This study showed that UC-MSCs transplantation could promote recovery of thin endometrial morphology and function. Furthermore, it revealed the expression changes of miRNA and mRNA after endometrial injury and UC-MSCs transplantation repair processed, and signaling pathways that may be involved in endometrial injury and repair.

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Repeated injections of human umbilical cord blood-derived mesenchymal stem cells significantly promotes functional recovery in rabbits with spinal cord injury of two noncontinuous segments.

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Repeated injections of human umbilical cord blood-derived mesenchymal stem cells significantly promotes functional recovery in rabbits with spinal cord injury of two noncontinuous segments.

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