TY - JOUR
T1 - Heparin-binding epidermal growth factor-like growth factor and mesenchymal stem cells act synergistically to prevent experimental necrotizing enterocolitis
AU - Yang, Jixin
AU - Watkins, Daniel
AU - Chen, Chun Liang
AU - Bhushan, Bharath
AU - Zhou, Yu
AU - Besner, Gail E.
N1 - Funding Information:
This work is supported by NIH R01 DK74611 and NIH R01 GM61193 (GEB).
PY - 2012/10
Y1 - 2012/10
N2 - Background: We have shown that administration of heparin-binding EGF (epidermal growth factor)-like growth factor (HB-EGF) protects the intestines from experimental necrotizing enterocolitis (NEC). We have also demonstrated that systemically administered mesenchymal stem cells (MSC) can engraft into injured intestines. This study investigated the effects of HB-EGF on MSC in vitro, and whether MSC and HB-EGF can act synergistically to prevent NEC in vivo. Study Design: In vitro, the effect of HB-EGF on MSC proliferation, migration, and apoptosis was determined. In vivo, rat pups received MSC either intraperitoneally (IP) or intravenously (IV). Pups were assigned to 1 of 7 groups: Group 1, breast-fed; Group 2, experimental NEC; Group 3, NEC+HB-EGF; Group 4, NEC+MSC IP; Group 5, NEC+HB-EGF+MSC IP; Group 6, NEC+MSC IV; or Group 7, NEC+HB-EGF+MSC IV. Mesechymal stem cell engraftment, histologic injury, intestinal permeability, and mortality were determined. Results: Heparin-binding EGF-like growth factor promoted MSC proliferation and migration, and decreased MSC apoptosis in vitro. In vivo, MSC administered IV had increased engraftment into NEC-injured intestine compared with MSC administered IP (p < 0.05). Heparin binding EGF-like growth factor increased engraftment of IP-administered MSC (p < 0.01) and IV-administered MSC (p < 0.05). Pups in Groups 3 to 7 had a decreased incidence of NEC compared with nontreated pups (Group 2), with the lowest incidence in pups treated with HB-EGF+MSC IV (p < 0.01). Pups in Group 7 had a significantly decreased incidence of intestinal dilation and perforation, and had the lowest intestinal permeability, compared with other treatment groups (p < 0.01). Pups in all experimental groups had significantly improved survival compared with pups exposed to NEC, with the best survival in Group 7 (p < 0.05). Conclusions: Heparin-binding EGF-like growth factor and MSC act synergistically to reduce injury and improve survival in experimental NEC.
AB - Background: We have shown that administration of heparin-binding EGF (epidermal growth factor)-like growth factor (HB-EGF) protects the intestines from experimental necrotizing enterocolitis (NEC). We have also demonstrated that systemically administered mesenchymal stem cells (MSC) can engraft into injured intestines. This study investigated the effects of HB-EGF on MSC in vitro, and whether MSC and HB-EGF can act synergistically to prevent NEC in vivo. Study Design: In vitro, the effect of HB-EGF on MSC proliferation, migration, and apoptosis was determined. In vivo, rat pups received MSC either intraperitoneally (IP) or intravenously (IV). Pups were assigned to 1 of 7 groups: Group 1, breast-fed; Group 2, experimental NEC; Group 3, NEC+HB-EGF; Group 4, NEC+MSC IP; Group 5, NEC+HB-EGF+MSC IP; Group 6, NEC+MSC IV; or Group 7, NEC+HB-EGF+MSC IV. Mesechymal stem cell engraftment, histologic injury, intestinal permeability, and mortality were determined. Results: Heparin-binding EGF-like growth factor promoted MSC proliferation and migration, and decreased MSC apoptosis in vitro. In vivo, MSC administered IV had increased engraftment into NEC-injured intestine compared with MSC administered IP (p < 0.05). Heparin binding EGF-like growth factor increased engraftment of IP-administered MSC (p < 0.01) and IV-administered MSC (p < 0.05). Pups in Groups 3 to 7 had a decreased incidence of NEC compared with nontreated pups (Group 2), with the lowest incidence in pups treated with HB-EGF+MSC IV (p < 0.01). Pups in Group 7 had a significantly decreased incidence of intestinal dilation and perforation, and had the lowest intestinal permeability, compared with other treatment groups (p < 0.01). Pups in all experimental groups had significantly improved survival compared with pups exposed to NEC, with the best survival in Group 7 (p < 0.05). Conclusions: Heparin-binding EGF-like growth factor and MSC act synergistically to reduce injury and improve survival in experimental NEC.
KW - 4,6-Diamidino-2-Phenylindole Dihydrochloride
KW - D-MEM
KW - DAPI
KW - Dulbecco's Modified Eagle Medium
KW - FD
KW - HB-EGF
KW - IP
KW - MSC
KW - NEC
KW - YFP
KW - fluorescein isothiocyanate (FITC)-labeled dextran
KW - heparin-binding epidermal growth factor-like growth factor
KW - intraperitoneal
KW - mesenchymal stem cells
KW - necrotizing enterocolitis
KW - yellow fluorescent protein
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U2 - 10.1016/j.jamcollsurg.2012.05.037
DO - 10.1016/j.jamcollsurg.2012.05.037
M3 - Article
C2 - 22819639
AN - SCOPUS:84866361378
SN - 1072-7515
VL - 215
SP - 534
EP - 545
JO - Journal of the American College of Surgeons
JF - Journal of the American College of Surgeons
IS - 4
ER -