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Bone Marrow-Derived Mesenchymal Stem Cells Repair Necrotic Pancreatic Tissue and Promote Angiogenesis by Secreting Cellular Growth Factors Involved in the SDF-1 α /CXCR4 Axis in Rats.

Qian D, Gong J, He Z, Hua J, Lin S, Xu C, Meng H, Song Z - Stem Cells Int (2015)

Bottom Line: We validated that SDF-1α significantly stimulated the expressions of VEGF, ANG-1, HGF, TGF-β, and CXCR4 in BMSCs, which were inhibited by its receptor agonist, AMD3100.In vivo, the migration of BMSCs was regulated by SDF-1α/CXCR4 axis.Moreover, transplanted BMSCs could significantly alleviate SAP, reduce the systematic inflammation (TNF-α↓, IL-1β↓, IL-6↓, IL-4↑, IL-10↑, and TGF-β↑), and promote tissue repair and angiogenesis (VEGF↑, ANG-1↑, HGF↑, TGF-β↑, and CD31↑), compared with the SAP and anti-CXCR4 groups.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University of Medicine, Shanghai 200072, China.

ABSTRACT
Acute pancreatitis (AP), a common acute abdominal disease, 10%-20% of which can evolve into severe acute pancreatitis (SAP), is of significant morbidity and mortality. Bone marrow-derived mesenchymal stem cells (BMSCs) have been reported to have a potential therapeutic role on SAP, but the specific mechanism is unclear. Therefore, we conducted this experiment to shed light on the probable mechanism. We validated that SDF-1α significantly stimulated the expressions of VEGF, ANG-1, HGF, TGF-β, and CXCR4 in BMSCs, which were inhibited by its receptor agonist, AMD3100. The capacities of proliferation, migration, and repair of human umbilical vein endothelial cells were enhanced by BMSCs supernatant. Meanwhile, BMSCs supernatant could also promote angiogenesis, especially after the stimulation with SDF-1α. In vivo, the migration of BMSCs was regulated by SDF-1α/CXCR4 axis. Moreover, transplanted BMSCs could significantly alleviate SAP, reduce the systematic inflammation (TNF-α↓, IL-1β↓, IL-6↓, IL-4↑, IL-10↑, and TGF-β↑), and promote tissue repair and angiogenesis (VEGF↑, ANG-1↑, HGF↑, TGF-β↑, and CD31↑), compared with the SAP and anti-CXCR4 groups. Taken together, the results showed that BMSCs ameliorated SAP and the SDF-1α/CXCR4 axis was involved in the repair and regeneration process.

No MeSH data available.


Related in: MedlinePlus

Prussian blue staining was performed for detecting the SPION-labeled BMSCs in pancreatic and lung tissues. (a) The Prussian blue staining of pancreatic tissue indicates that the cells were stained blue (as indicated by black arrows), gradually increased, and peaked on postoperative days 5–7, when the formation of tubular complexes was also maximal (as indicated by red arrows). However, the migration was partly inhibited and the trend was not obviously investigated in anti-CXCR4 group. (b) The lung tissues were stained by Prussian blue and the blue particles (as indicated by black arrows) were gradually decreasing in both BMSCs and anti-CXCR4 groups. (c) The blue particles in lung, pancreas, liver, spleen, and small intestine were counted and analyzed between BMSCs and anti-CXCR4 groups. The result showed that the number of blue particles of pancreas in BMSCs group was significantly more than in anti-CXCR4 group at postoperative days 1, 3, 5, and 7. Data are expressed as mean ± SD (**P < 0.01 and ***P < 0.001 for BMSCs versus anti-CXCR4 at each corresponding time point).
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fig4: Prussian blue staining was performed for detecting the SPION-labeled BMSCs in pancreatic and lung tissues. (a) The Prussian blue staining of pancreatic tissue indicates that the cells were stained blue (as indicated by black arrows), gradually increased, and peaked on postoperative days 5–7, when the formation of tubular complexes was also maximal (as indicated by red arrows). However, the migration was partly inhibited and the trend was not obviously investigated in anti-CXCR4 group. (b) The lung tissues were stained by Prussian blue and the blue particles (as indicated by black arrows) were gradually decreasing in both BMSCs and anti-CXCR4 groups. (c) The blue particles in lung, pancreas, liver, spleen, and small intestine were counted and analyzed between BMSCs and anti-CXCR4 groups. The result showed that the number of blue particles of pancreas in BMSCs group was significantly more than in anti-CXCR4 group at postoperative days 1, 3, 5, and 7. Data are expressed as mean ± SD (**P < 0.01 and ***P < 0.001 for BMSCs versus anti-CXCR4 at each corresponding time point).

Mentions: The results of Prussian blue staining showed that the SPION-labeled BMSCs were relatively low in pancreas, liver, spleen, and small intestine at the first day of the transplant compared to lung, but gradually increasing in pancreatic tissue at posttransplant days 3 and 7 and relatively high compared to liver, spleen, and small intestine, when the formation of tubular complexes (TCs) was also maximal (Figures 4(a)–4(c)). On the contrary, SPION-labeled BMSCs in the lung tissue became less and less (Figure 5(b)). The more important point was that the migrations of SPION-labeled BMSCs to injured pancreas could be inhibited by anti-CXCR4 treatment (Figures 4(a)–4(c)). To further visually investigate whether the SPION-labeled BMSCs could migrate to injured pancreas, the MRI method was selected for realizing the tracing in vivo. The magnetic resonance images displayed that SPION-labeled BMSCs ([Fe3+] = 25 g/mL) were high signal in T1WI (white) and low signal (dark) in T2WI as shown in Figure 5(a). The high signal intensity (white points) in pancreas (as indicated by red circle) increased gradually in T1WI and peaked on days 5 and 7 (Figure 5(b)). We also performed T2WI on day 7 in order to exclude the possibility of false positive and the result showed that the high signals (white points) in T1WI became low signals (dark points) in T2WI, whereas the low signals (dark points) in T1WI became high signals (white points) as shown in Figure 5(c). Furthermore, the high signals in T1WI decreased obviously in anti-CXCR4 group compared with BMSCs group on posttransplant day 5 (Figure 5(b)).


Bone Marrow-Derived Mesenchymal Stem Cells Repair Necrotic Pancreatic Tissue and Promote Angiogenesis by Secreting Cellular Growth Factors Involved in the SDF-1 α /CXCR4 Axis in Rats.

Qian D, Gong J, He Z, Hua J, Lin S, Xu C, Meng H, Song Z - Stem Cells Int (2015)

Prussian blue staining was performed for detecting the SPION-labeled BMSCs in pancreatic and lung tissues. (a) The Prussian blue staining of pancreatic tissue indicates that the cells were stained blue (as indicated by black arrows), gradually increased, and peaked on postoperative days 5–7, when the formation of tubular complexes was also maximal (as indicated by red arrows). However, the migration was partly inhibited and the trend was not obviously investigated in anti-CXCR4 group. (b) The lung tissues were stained by Prussian blue and the blue particles (as indicated by black arrows) were gradually decreasing in both BMSCs and anti-CXCR4 groups. (c) The blue particles in lung, pancreas, liver, spleen, and small intestine were counted and analyzed between BMSCs and anti-CXCR4 groups. The result showed that the number of blue particles of pancreas in BMSCs group was significantly more than in anti-CXCR4 group at postoperative days 1, 3, 5, and 7. Data are expressed as mean ± SD (**P < 0.01 and ***P < 0.001 for BMSCs versus anti-CXCR4 at each corresponding time point).
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig4: Prussian blue staining was performed for detecting the SPION-labeled BMSCs in pancreatic and lung tissues. (a) The Prussian blue staining of pancreatic tissue indicates that the cells were stained blue (as indicated by black arrows), gradually increased, and peaked on postoperative days 5–7, when the formation of tubular complexes was also maximal (as indicated by red arrows). However, the migration was partly inhibited and the trend was not obviously investigated in anti-CXCR4 group. (b) The lung tissues were stained by Prussian blue and the blue particles (as indicated by black arrows) were gradually decreasing in both BMSCs and anti-CXCR4 groups. (c) The blue particles in lung, pancreas, liver, spleen, and small intestine were counted and analyzed between BMSCs and anti-CXCR4 groups. The result showed that the number of blue particles of pancreas in BMSCs group was significantly more than in anti-CXCR4 group at postoperative days 1, 3, 5, and 7. Data are expressed as mean ± SD (**P < 0.01 and ***P < 0.001 for BMSCs versus anti-CXCR4 at each corresponding time point).
Mentions: The results of Prussian blue staining showed that the SPION-labeled BMSCs were relatively low in pancreas, liver, spleen, and small intestine at the first day of the transplant compared to lung, but gradually increasing in pancreatic tissue at posttransplant days 3 and 7 and relatively high compared to liver, spleen, and small intestine, when the formation of tubular complexes (TCs) was also maximal (Figures 4(a)–4(c)). On the contrary, SPION-labeled BMSCs in the lung tissue became less and less (Figure 5(b)). The more important point was that the migrations of SPION-labeled BMSCs to injured pancreas could be inhibited by anti-CXCR4 treatment (Figures 4(a)–4(c)). To further visually investigate whether the SPION-labeled BMSCs could migrate to injured pancreas, the MRI method was selected for realizing the tracing in vivo. The magnetic resonance images displayed that SPION-labeled BMSCs ([Fe3+] = 25 g/mL) were high signal in T1WI (white) and low signal (dark) in T2WI as shown in Figure 5(a). The high signal intensity (white points) in pancreas (as indicated by red circle) increased gradually in T1WI and peaked on days 5 and 7 (Figure 5(b)). We also performed T2WI on day 7 in order to exclude the possibility of false positive and the result showed that the high signals (white points) in T1WI became low signals (dark points) in T2WI, whereas the low signals (dark points) in T1WI became high signals (white points) as shown in Figure 5(c). Furthermore, the high signals in T1WI decreased obviously in anti-CXCR4 group compared with BMSCs group on posttransplant day 5 (Figure 5(b)).

Bottom Line: We validated that SDF-1α significantly stimulated the expressions of VEGF, ANG-1, HGF, TGF-β, and CXCR4 in BMSCs, which were inhibited by its receptor agonist, AMD3100.In vivo, the migration of BMSCs was regulated by SDF-1α/CXCR4 axis.Moreover, transplanted BMSCs could significantly alleviate SAP, reduce the systematic inflammation (TNF-α↓, IL-1β↓, IL-6↓, IL-4↑, IL-10↑, and TGF-β↑), and promote tissue repair and angiogenesis (VEGF↑, ANG-1↑, HGF↑, TGF-β↑, and CD31↑), compared with the SAP and anti-CXCR4 groups.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University of Medicine, Shanghai 200072, China.

ABSTRACT
Acute pancreatitis (AP), a common acute abdominal disease, 10%-20% of which can evolve into severe acute pancreatitis (SAP), is of significant morbidity and mortality. Bone marrow-derived mesenchymal stem cells (BMSCs) have been reported to have a potential therapeutic role on SAP, but the specific mechanism is unclear. Therefore, we conducted this experiment to shed light on the probable mechanism. We validated that SDF-1α significantly stimulated the expressions of VEGF, ANG-1, HGF, TGF-β, and CXCR4 in BMSCs, which were inhibited by its receptor agonist, AMD3100. The capacities of proliferation, migration, and repair of human umbilical vein endothelial cells were enhanced by BMSCs supernatant. Meanwhile, BMSCs supernatant could also promote angiogenesis, especially after the stimulation with SDF-1α. In vivo, the migration of BMSCs was regulated by SDF-1α/CXCR4 axis. Moreover, transplanted BMSCs could significantly alleviate SAP, reduce the systematic inflammation (TNF-α↓, IL-1β↓, IL-6↓, IL-4↑, IL-10↑, and TGF-β↑), and promote tissue repair and angiogenesis (VEGF↑, ANG-1↑, HGF↑, TGF-β↑, and CD31↑), compared with the SAP and anti-CXCR4 groups. Taken together, the results showed that BMSCs ameliorated SAP and the SDF-1α/CXCR4 axis was involved in the repair and regeneration process.

No MeSH data available.


Related in: MedlinePlus