Paradoxical Effects of PDGF-BB Overexpression in Endothelial Cells on Engineered Blood Vessels In Vivo

Au, Patrick; Tam, Joshua; Duda, Dan G.; Lin, Pei‐Chun; Munn, Lance L.; Jain, Rakesh K.

doi:10.2353/ajpath.2009.080887

Cited by 40 publications

(28 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, we showed that apoptosis of PDGFR-β + MSCs preceded the infiltration of host vasculature into the implants, and thus the initial provision of ECFCs was indeed critical. Also, although simply adding exogenous PDGF-BB reduces MSC apoptosis, unregulated provision of PDGF-BB in vivo could be detrimental and produce vascular regression (22). This regression does not occur with ECFCs, which can modulate in a timely way the delivery of PDGF-BB and other paracrine factors during their interaction with MSCs.…”

Section: Discussionmentioning

confidence: 99%

Human endothelial colony-forming cells serve as trophic mediators for mesenchymal stem cell engraftment via paracrine signaling

Lin

Moreno‐Luna

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

139

112

View full text Add to dashboard Cite

Endothelial colony-forming cells (ECFCs) are endothelial precursors that circulate in peripheral blood. Studies have demonstrated that human ECFCs have robust vasculogenic properties. However, whether ECFCs can exert trophic functions in support of specific stem cells in vivo remains largely unknown. Here, we sought to determine whether human ECFCs can function as paracrine mediators before the establishment of blood perfusion. We used two xenograft models of human mesenchymal stem cell (MSC) transplantation and studied how the presence of ECFCs modulates MSC engraftment and regenerative capacity in vivo. Human MSCs were isolated from white adipose tissue and bone marrow aspirates and were s.c. implanted into immunodeficient mice in the presence or absence of cord blood-derived ECFCs. MSC engraftment was regulated by ECFC-derived paracrine factors via platelet-derived growth factor BB (PDGF-BB)/platelet-derived growth factor receptor (PDGFR)-β signaling. Cotransplanting ECFCs significantly enhanced MSC engraftment by reducing early apoptosis and preserving stemness-related properties of PDGFR-β + MSCs, including the ability to repopulate secondary grafts. MSC engraftment was negligible in the absence of ECFCs and completely impaired in the presence of Tyrphostin AG1296, an inhibitor of PDGFR kinase. Additionally, transplanted MSCs displayed fate-restricted potential in vivo, with adipose tissue-derived and bone marrow-derived MSCs contributing exclusive differentiation along adipogenic and osteogenic lineages, respectively. This work demonstrates that blood-derived ECFCs can serve as paracrine mediators and regulate the regenerative potential of MSCs via PDGF-BB/PDGFR-β signaling. Our data suggest the systematic use of ECFCs as a means to improve MSC transplantation.vasculogenesis | adipogenesis | osteogenesis | angiocrine factors

show abstract

Section: Discussionmentioning

confidence: 99%

Human endothelial colony-forming cells serve as trophic mediators for mesenchymal stem cell engraftment via paracrine signaling

Lin

Moreno‐Luna

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

139

112

View full text Add to dashboard Cite

show abstract

“…[12][13][14][15] PDGF over expression in endothelial cells, however, paradoxically promotes vascular rarefaction, suggesting that pro-apoptotic factors are released from, or survival factors are down-regulated in, expanded pericytes/fibroblasts. 16 Although vascular endothelial growth factor (VEGF) signaling from pericytes to endothelial cells has been implicated in developmental angiogenesis, [17][18][19] and more recently VEGF signaling from the specialized pericytes of the kidney glomerulus known as podocytes has been shown to be crucial for vascular stabilization, 20 the presence of VEGF receptor 1 (VEGFR1) FMS-like tyrosine kinase 1 (Flt1) and receptor 2 (VEGFR2) VEGF receptor 3 and Neuropilin 1 on endothelial cells, the regulated expression of four distinct VEGF genes, and the regulated expression of multiple transcription splice variants render VEGF signaling more complicated than simple binary ligand-receptor interactions.…”

mentioning

confidence: 99%

Targeting Endothelium-Pericyte Cross Talk by Inhibiting VEGF Receptor Signaling Attenuates Kidney Microvascular Rarefaction and Fibrosis

Lin

Chang

Schrimpf

et al. 2011

The American Journal of Pathology

233

287

View full text Add to dashboard Cite

Microvascular pericytes and perivascular fibroblasts have recently been identified as the source of scar-producing myofibroblasts that appear after injury of the kidney. We show that cross talk between pericytes and endothelial cells concomitantly dictates development of fibrosis and loss of microvasculature after injury. When either platelet-derived growth factor receptor (R)-␤ signaling in pericytes or vascular endothelial growth factor (VEGF)R2 signaling in endothelial cells was blocked by circulating soluble receptor ectodomains, both fibrosis and capillary rarefaction were markedly attenuated during progressive kidney injury. Blockade of either receptor-mediated signaling pathway prevented pericyte differentiation and proliferation, but VEGFR2 blockade also attenuated recruitment of inflammatory macrophages throughout disease progression. Whereas injury down-regulated angiogenic VEGF164, the dys-angiogenic isomers VEGF120 and VEGF188 were up-regulated, suggesting that pericyte-myofibroblast differentiation triggers endothelial loss by a switch in secretion of VEGF isomers. These findings link fibrogenesis inextricably with microvascular rarefaction for the first time, add new significance to fibrogenesis, and identify novel therapeutic targets. (Am J Pathol 2011, 178:911-923;

show abstract

“…However, the incorporation of growth factors is extremely complicated as it concerns dosage and combinations [40]. Au et al reported a regression of the microvascular network with the use of angiogenic growth factors in combination with vascular cells [41]. Also, normally proangiogenic nitric oxide showed a converse effect under certain conditions [40].…”

Section: Discussionmentioning

confidence: 99%

“…The application of VEGF could also expedite vascularization in the ischemic hindlimb model of diabetic mice [52]. However, with regards to the multiple problems associated with the treatment with growth factors [40][41][42][43], they were not used in the current investigation.…”

Section: Discussionmentioning

confidence: 99%

Decelerated vascularization in tissue-engineered constructs in association with diabetes mellitus in vivo

Schumann¹,

Lindhorst²,

Kampmann³

et al. 2015

Journal of Diabetes and its Complications

View full text Add to dashboard Cite

Paradoxical Effects of PDGF-BB Overexpression in Endothelial Cells on Engineered Blood Vessels In Vivo

Cited by 40 publications

References 33 publications

Human endothelial colony-forming cells serve as trophic mediators for mesenchymal stem cell engraftment via paracrine signaling

Human endothelial colony-forming cells serve as trophic mediators for mesenchymal stem cell engraftment via paracrine signaling

Targeting Endothelium-Pericyte Cross Talk by Inhibiting VEGF Receptor Signaling Attenuates Kidney Microvascular Rarefaction and Fibrosis

Decelerated vascularization in tissue-engineered constructs in association with diabetes mellitus in vivo

Contact Info

Product

Resources

About