Bone marrow mesenchymal stem cell transplantation downregulates plasma level and the microglia expression of transforming growth factor β1 in the acute phase of cerebral cortex ischemia

Abstract

Background Both bone marrow mesenchymal stem cell (BM-MSC) and transforming growth factor-β1 (TGF-β1) have a strong anti-inflammatory capacity in stroke. But their relationship has not been well addressed. In this study, we investigated how intravenous BM-MSC transplantation in rats effected the expression of TGF-β1 48 h post cerebral ischemia, and we analyzed the main cells that produce TGF-β1. Methods We used a distal middle cerebral artery occlusion (dMCAO) model in twenty Sprague–Dawley (SD) rats. The rats were randomly divided into two groups: the ischemic control group and the postischemic BM-MSC transplantation group. One hour after the dMCAO model was established, the rats were injected in the tail vein with either 1 ml saline or 1 × 10 6 BM-MSCs suspended in 1 ml saline. ELISAs were used to detect TGF-β1 content in the brain infarct core area, striatum and the plasma at 48 h after cerebral infarction. Immunofluorescent staining of brain tissue sections for TGF-β1, Iba-1, CD68 and NeuN was performed to determine the number and the proportion of double stained cells and to detect possible TGF-β1 producing cells in the brain tissue. Results Forty-eight hours after ischemia, the TGF-β1 content in the infarcted area of the BM-MSC transplantation group (23.94 ± 4.48 pg/ml) was significantly lower than it was in the ischemic control group (34.18 ± 4.32 pg/ml) (F = 13.534, P = 0.006). The TGF-β1 content in the rat plasma in the BM-MSC transplantation group (75.91 ± 12.53 pg/ml) was significantly lower than it was in the ischemic control group (131.18 ± 16.07 pg/ml) (F = 36.779, P = 0.0002), suggesting that after transplantation of BM-MSCs, TGF-β1 levels in the plasma decreased, but there was no significant change in the striatum area. Immunofluorescence staining showed that the total number of nucleated cells (1037.67 ± 222.16 cells/mm 2 ) in the infarcted area after transplantation was significantly higher than that in the ischemic control group (391.67 ± 69.50 cells/mm 2 ) (F = 92.421, P < 0.01); the number of TGF-β1 + cells after transplantation (35.00 ± 13.66 cells/mm 2 ) was significantly reduced in comparison to that in the ischemic control group (72.33 ± 32.08 cells/mm 2 ) (F = 37.680, P < 0.01). The number of TGF-β1 + /Iba-1 + microglia cells in the transplantation group (3.67 ± 3.17 cells/mm 2 ) was significantly reduced in comparison to that of the ischemic control group (13.67 ± 5.52 cells/mm 2 ) (F = 29.641, P < 0.01). The proportion of TGF-β1 + /Iba-1 + microglia cells out ...

The double-edged sword of transforming growth factor β 1: a systematic review of pre-clinical stroke models

“…117 full-text articles were assessed for inclusion, with 28 excluded (Figure 1). Three of these were excluded due to use of an inappropriate model [30][31][32] , two for being performed in vitro 33,34 , two due to not being relevant to TGF-β1 35,36 , eight for not having a full text available [37][38][39][40][41][42][43][44] , one due to a lack of experimental controls 45 and 12 for measuring inappropriate outcomes or measuring TGF-β1 as part of a large panel of molecules [46][47][48][49][50][51][52][53][54][55][56][57] A further four studies used photothrombosis to induce focal cortical ischemia following administration of a photosensitizing agent, whilst two studies utilized the injection of autologous blood clots to the internal carotid artery.…”

Modulatory effects of mesenchymal stem cells on microglia in ischemic stroke

“…These results indicated that MSC could also be developed as a prophylactic therapy for patients post-stroke besides therapeutic treatment. Most preclinical studies showed that the number of activated microglia was significantly decreased by MSC or EV administration ( 15 , 61 , 63 – 65 , 75 , 77 – 82 , 84 , 85 , 88 ). Notably, three-dimensional (3D) spheroid cultured MSCs have been demonstrated to exhibit decreased cell size; therefore, these cells are not likely to be entrapped in lung tissue after IV infusion ( 39 ).…”

“…Compared with 7 days post-ischemia, administration of either allogeneic (rMSCs) or xenogeneic (hMSCs) stem cells at 1 day resulted in a significantly greater recovery of motor behavior after MCAO that was possibly related to an increase in activated microglia (CD11) in the infarct region ( 76 ). Transplantation of BMSC reduces the proportion of Iba-1 + microglia cells expressing TGF-β in the cerebral infarction area 48 h after ischemia ( 88 ). IV allogenic BMSC significantly increased the inflammation, evidenced by an increase of TNFαand IL-1βand the number of Iba+ microglia/macrophages in the ischemic core cortex at day 2 after MCAO ( 83 ).…”

“…IV allogenic BMSC significantly increased the inflammation, evidenced by an increase of TNFαand IL-1βand the number of Iba+ microglia/macrophages in the ischemic core cortex at day 2 after MCAO ( 83 ). Hence, MSC delivered at 2 days after MCAO can stimulate but not suppress the immune response ( 83 , 88 ). It is reasonable that the immunosuppressive capacity of MSC requires a certain amount of time to be induced under inflammatory conditions.…”

Identification of the genetic central dogma in osteogenic differentiation of MSCs by osteoinductive medium from transcriptional data sets

“…For decades, mesenchymal stem cells (MSCs) have been demonstrated their multiple differentiation capacities into bone tissue, cartilage tissue, and their clinical treatment potential on a variety of disease such as cerebral infarction. 1 , 2 , 3 In the case of osteogenic differentiation of MSCs, there are numerous methods and specific ways that can successfully induce MSCs differentiating into osteoblastic linage, including osteoinduction media, pharmaceuticals, growth factors, genes, biomaterials, even mechanical stress stimulations, when used singly or combined together. 4 , 5 , 6 , 7 Yet, there is still a lack of knowledge for understanding the mechanism of how MSCs differentiate into osteogenic linage cells under these massive conditions.…”