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Genetically modified human placenta‑derived mesenchymal stem cells with FGF‑2 and PDGF‑BB enhance neovascularization in a model of hindlimb ischemia.

Yin T, He S, Su C, Chen X, Zhang D, Wan Y, Ye T, Shen G, Wang Y, Shi H, Yang L, Wei Y - Mol Med Rep (2015)

Bottom Line: Mesenchymal stem cells obtained from human term placenta were transfected ex vivo with adenoviral bicistronic vectors carrying the FGF2 and PDGF‑BB genes (Ad‑F‑P).Histological examination revealed markedly increased capillary and arteriole density in the Ad‑F‑P‑hPDMSC group.The current study demonstrated that the combination of hPDMSC therapy with FGF2 and PDGF‑BB gene therapy effectively induced collateral vessel formation and angiogenesis, suggesting a novel strategy for therapeutic angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, P.R. China.

ABSTRACT
Ischemic diseases represent a challenging worldwide health burden. The current study investigated the therapeutic potential of genetically modified human placenta‑derived mesenchymal stem cells (hPDMSCs) with basic fibroblast growth factor (FGF2) and platelet‑derived growth factor‑BB (PDGF‑BB) genes in hindlimb ischemia. Mesenchymal stem cells obtained from human term placenta were transfected ex vivo with adenoviral bicistronic vectors carrying the FGF2 and PDGF‑BB genes (Ad‑F‑P). Unilateral hindlimb ischemia was surgically induced by excision of the right femoral artery in New Zealand White rabbits. Ad‑F‑P genetically modified hPDMSCs, Ad‑ (control vector)‑modified hPDMSCs, unmodified hPDMSCs or media were intramuscularly implanted into the ischemic limbs 7 days subsequent to the induction of ischemia. Four weeks after cell therapy, angiographic analysis revealed significantly increased collateral vessel formation in the Ad‑F‑P‑hPDMSC group compared with the control group. Histological examination revealed markedly increased capillary and arteriole density in the Ad‑F‑P‑hPDMSC group. The xenografted hPDMSCs survived in the ischemic tissue for at least 4 weeks subsequent to cell therapy. The current study demonstrated that the combination of hPDMSC therapy with FGF2 and PDGF‑BB gene therapy effectively induced collateral vessel formation and angiogenesis, suggesting a novel strategy for therapeutic angiogenesis.

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Assessment of mature arterioles. (A) Ischemic muscle sections were stained with antibody against αSMA to evaluate arteriole maturation. More αSMA + mural cell-covered arterioles were observed in Ad-F-P-hPDMSCs group. Scale bar, 50 µm. (B) Quantification of mature arterioles in ischemic muscles. Genetically-modified hPDMSCs significantly increased mature artery formation. *P<0.05 vs. control. αSMA, α smooth muscle actin; hPDMSC, human placenta-derived mesenchymal stem cell; AD-F-P, adenoviral bicistronic vector containing FGF2 and PDGF-BB; Ad-, control vector; ctrl, control without PDMSCs.
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f3-mmr-12-04-5093: Assessment of mature arterioles. (A) Ischemic muscle sections were stained with antibody against αSMA to evaluate arteriole maturation. More αSMA + mural cell-covered arterioles were observed in Ad-F-P-hPDMSCs group. Scale bar, 50 µm. (B) Quantification of mature arterioles in ischemic muscles. Genetically-modified hPDMSCs significantly increased mature artery formation. *P<0.05 vs. control. αSMA, α smooth muscle actin; hPDMSC, human placenta-derived mesenchymal stem cell; AD-F-P, adenoviral bicistronic vector containing FGF2 and PDGF-BB; Ad-, control vector; ctrl, control without PDMSCs.

Mentions: FGF2 and PDGF have been demonstrated to establish stable and mature vessels associated with recruitment of mural cells (12). To further determine whether Ad-F-P-hPDMSCs are able to promote mature arteriole formation, muscle sections were stained with antibodies against αSMA. The arteriole density was higher in the Ad-F-P-hPDMSC group compared with that of other groups (Fig. 3A). An increase in αSMA-covered vessels was observed in the Ad-F-P-hPDMSC group. However, there was no significant difference between the Ad--hPDMSC, hPDMSC and control groups in the arteriole density (Fig. 3B). These results suggest that Ad-F-P-hPDMSCs promote arteriole maturation in ischemic areas.


Genetically modified human placenta‑derived mesenchymal stem cells with FGF‑2 and PDGF‑BB enhance neovascularization in a model of hindlimb ischemia.

Yin T, He S, Su C, Chen X, Zhang D, Wan Y, Ye T, Shen G, Wang Y, Shi H, Yang L, Wei Y - Mol Med Rep (2015)

Assessment of mature arterioles. (A) Ischemic muscle sections were stained with antibody against αSMA to evaluate arteriole maturation. More αSMA + mural cell-covered arterioles were observed in Ad-F-P-hPDMSCs group. Scale bar, 50 µm. (B) Quantification of mature arterioles in ischemic muscles. Genetically-modified hPDMSCs significantly increased mature artery formation. *P<0.05 vs. control. αSMA, α smooth muscle actin; hPDMSC, human placenta-derived mesenchymal stem cell; AD-F-P, adenoviral bicistronic vector containing FGF2 and PDGF-BB; Ad-, control vector; ctrl, control without PDMSCs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581748&req=5

f3-mmr-12-04-5093: Assessment of mature arterioles. (A) Ischemic muscle sections were stained with antibody against αSMA to evaluate arteriole maturation. More αSMA + mural cell-covered arterioles were observed in Ad-F-P-hPDMSCs group. Scale bar, 50 µm. (B) Quantification of mature arterioles in ischemic muscles. Genetically-modified hPDMSCs significantly increased mature artery formation. *P<0.05 vs. control. αSMA, α smooth muscle actin; hPDMSC, human placenta-derived mesenchymal stem cell; AD-F-P, adenoviral bicistronic vector containing FGF2 and PDGF-BB; Ad-, control vector; ctrl, control without PDMSCs.
Mentions: FGF2 and PDGF have been demonstrated to establish stable and mature vessels associated with recruitment of mural cells (12). To further determine whether Ad-F-P-hPDMSCs are able to promote mature arteriole formation, muscle sections were stained with antibodies against αSMA. The arteriole density was higher in the Ad-F-P-hPDMSC group compared with that of other groups (Fig. 3A). An increase in αSMA-covered vessels was observed in the Ad-F-P-hPDMSC group. However, there was no significant difference between the Ad--hPDMSC, hPDMSC and control groups in the arteriole density (Fig. 3B). These results suggest that Ad-F-P-hPDMSCs promote arteriole maturation in ischemic areas.

Bottom Line: Mesenchymal stem cells obtained from human term placenta were transfected ex vivo with adenoviral bicistronic vectors carrying the FGF2 and PDGF‑BB genes (Ad‑F‑P).Histological examination revealed markedly increased capillary and arteriole density in the Ad‑F‑P‑hPDMSC group.The current study demonstrated that the combination of hPDMSC therapy with FGF2 and PDGF‑BB gene therapy effectively induced collateral vessel formation and angiogenesis, suggesting a novel strategy for therapeutic angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, P.R. China.

ABSTRACT
Ischemic diseases represent a challenging worldwide health burden. The current study investigated the therapeutic potential of genetically modified human placenta‑derived mesenchymal stem cells (hPDMSCs) with basic fibroblast growth factor (FGF2) and platelet‑derived growth factor‑BB (PDGF‑BB) genes in hindlimb ischemia. Mesenchymal stem cells obtained from human term placenta were transfected ex vivo with adenoviral bicistronic vectors carrying the FGF2 and PDGF‑BB genes (Ad‑F‑P). Unilateral hindlimb ischemia was surgically induced by excision of the right femoral artery in New Zealand White rabbits. Ad‑F‑P genetically modified hPDMSCs, Ad‑ (control vector)‑modified hPDMSCs, unmodified hPDMSCs or media were intramuscularly implanted into the ischemic limbs 7 days subsequent to the induction of ischemia. Four weeks after cell therapy, angiographic analysis revealed significantly increased collateral vessel formation in the Ad‑F‑P‑hPDMSC group compared with the control group. Histological examination revealed markedly increased capillary and arteriole density in the Ad‑F‑P‑hPDMSC group. The xenografted hPDMSCs survived in the ischemic tissue for at least 4 weeks subsequent to cell therapy. The current study demonstrated that the combination of hPDMSC therapy with FGF2 and PDGF‑BB gene therapy effectively induced collateral vessel formation and angiogenesis, suggesting a novel strategy for therapeutic angiogenesis.

Show MeSH
Related in: MedlinePlus