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

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.

GIT1 regulates angiogenic factor secretion in bone marrow mesenchymal stem cells via NF‐κB/Notch signalling to promote angiogenesis

“…In the present study, we found that GIT1 KO reduced the expression and secretion of angiogenic factors (VEGF, Ang‐1, FGF, HGF and TGF‐β) in BMSCs. Indeed, MSCs and its secreted angiogenic mediators have been shown to induce angiogenesis and thereby enhancing tissue repair and functional outcomes in a variety of pathologies associated with insufficient angiogenesis . Moreover, VEGF functions not only as one of the most important regulators of vascular development and angiogenesis, it also plays critical roles in skeletal development, which is consistent with our qPCR results in vivo and vitro.…”

Bone marrow-derived mesenchymal stem cells (BMSCs) repair acute necrotized pancreatitis by secreting microRNA-9 to target the NF-κB1/p50 gene in rats

“…The AP models were induced by the peritoneal injection of Caerulein ( 100 ug/kg ) for three times or the retrograde injection of 3% NaT ( 1   ml/kg ) as previously described 21, 26, 65 . All the procedures conform to Shanghai Laboratory Animal Ordinance and are approved by the Ethics of Shanghai Tenth People’s Hospital, affiliated to Tongji University ( Shanghai, China ).…”

“…Rats were randomly injected by the tail vein with pri-miR-9-BMSCs, Empty virus-BMSCs, TuD-BMSCs or BMSCs (1 × 10 7 cells/kg ) at postoperative day 1 as previously described 26 and thus divided into NC ( n   =   6 ), Sham ( n  =  6 ), SAP ( n  =  6 ), SAP+PBS (PBS treatment) ( n  =  6 ), BMSCs ( n  =  6 ), pri-miR-9-BMSCs ( n  =  6 ), Empty virus-BMSCs ( n  =  6 ), TuD-BMSCs ( n  =  6 ). In addition, to reveal the relationship between miR-9 and AP, we established several AP models as follows: NC ( n  =  3 ), Sham ( n  =  3 ), Caerulein ( n  =  3 ), 3% NaT ( n  =  3 ).…”

Mesenchymal stem cell therapy for acute and chronic pancreatitis

“…Another mechanism of MSCs for suppressing inflammation in AP is the anti-apoptosis effect [32,33]. MSCs promote repair and angiogenesis via the stromal cell derived factor (SDF)-1a/C-X-C chemokine receptor type 4 (CXCR4) axis [34]. The precise mechanism remains controversial, but several bioactive molecules secreted by MSCs have important roles.…”