scholarly journals Robust Angiogenesis and Arteriogenesis in the Skin of Diabetic Mice by Transient Delivery of Engineered VEGF and PDGF-BB Proteins in Fibrin Hydrogels

2021 ◽  
Vol 9 ◽  
Author(s):  
Alessandro Certelli ◽  
Paolo Valente ◽  
Andrea Uccelli ◽  
Andrea Grosso ◽  
Nunzia Di Maggio ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Delivery ◽  
Therapeutic Potential ◽  
Mouse Skin ◽  
Diabetic Mouse ◽  
Similar Efficacy ◽  
Therapeutic Window ◽  
Littermate Control ◽  
Normal Littermate ◽  
Endothelial Growth Factor

Non-healing ulcers are a serious complication of diabetes mellitus and a major unmet medical need. A major cause for the lack of healing is the impairment of spontaneous vascularization in the skin, despite mostly normal blood flow in deeper large vessels. Therefore, pro-angiogenic treatments are needed to increase therapeutic perfusion by recruiting new arterial connections (therapeutic arteriogenesis). Vascular endothelial growth factor (VEGF) is the master regulator of angiogenesis in physiology and disease, but exploitation of its therapeutic potential requires careful control of its dose distribution in tissue. Co-delivery of platelet derived growth factor-BB (PDGF-BB) has been shown to expand the therapeutic window of VEGF and also improve associated arteriogenesis. We used a highly controlled protein delivery system, based on a clinically applicable fibrin-based platform, to investigate the angiogenic and arteriogenic potential of engineered versions (TG-) of VEGF and PDGF-BB proteins in the skin of diabetic and obese db/db mice. Intradermal delivery of therapeutically relevant doses of TG-VEGF and TG-PDGF-BB induced robust growth of new microvascular networks with similar efficacy as in normal littermate control mice. Further, TG-PDGF-BB prevented the formation of aberrant vascular enlargements by high TG-VEGF levels. As fibrin was degraded after the first week, the induced angiogenesis mostly regressed by 4 weeks, but it promoted effective arteriogenesis in the dermal layer. Therefore, controlled co-delivery of TG-VEGF and TG-PDGF-BB recombinant proteins is effective to induce angiogenesis and arteriogenesis in diabetic mouse skin and should be further investigated to promote diabetic wound healing.

scholarly journals Macrophage-Derived Inflammation Induces a Transcriptome Makeover in Mesenchymal Stromal Cells Enhancing Their Potential for Tissue Repair

2021 ◽  
Vol 22 (2) ◽  
pp. 781
Author(s):  
Inés Maldonado-Lasunción ◽  
Nick O’Neill ◽  
Oliver Umland ◽  
Joost Verhaagen ◽  
Martin Oudega
Keyword(s):  
Growth Factor ◽  
Tissue Repair ◽  
Therapeutic Potential ◽  
Vascular Endothelial ◽  
Glial Derived Neurotrophic Factor ◽  
Transcriptomic Changes ◽  
Endothelial Growth Factor ◽  
Cellular Components ◽  
Hepatocyte Growth ◽  
Go Terms

Pre-clinical and clinical studies revealed that mesenchymal stromal cell (MSC) transplants elicit tissue repair. Conditioning MSC prior to transplantation may boost their ability to support repair. We investigated macrophage-derived inflammation as a means to condition MSC by comprehensively analyzing their transcriptome and secretome. Conditioning MSC with macrophage-derived inflammation resulted in 3208 differentially expressed genes, which were annotated with significantly enriched GO terms for 1085 biological processes, 85 cellular components, and 79 molecular functions. Inflammation-mediated conditioning increased the secretion of growth factors that are key for tissue repair, including vascular endothelial growth factor, hepatocyte growth factor, nerve growth factor and glial-derived neurotrophic factor. Furthermore, we found that inflammation-mediated conditioning induces transcriptomic changes that challenge the viability and mobility of MSC. Our data support the notion that macrophage-derived inflammation stimulates MSC to augment their paracrine repair-supporting activity. The results suggest that inflammatory pre-conditioning enhances the therapeutic potential of MSC transplants.

scholarly journals Physoxia alters human mesenchymal stem cell secretome

2021 ◽  
Vol 12 ◽  
pp. 204173142110561
Author(s):  
Marwan M Merkhan ◽  
Matthew T Shephard ◽  
Nicholas R Forsyth
Keyword(s):  
Stem Cell ◽  
Growth Factor ◽  
Mesenchymal Stem Cell ◽  
Therapeutic Potential ◽  
Interleukin 2 ◽  
Human Mesenchymal Stem Cell ◽  
Total Protein Content ◽  
Necrosis Factor Alpha ◽  
Oxygen Conditions ◽  
Endothelial Growth Factor

The human mesenchymal stem cell (hMSC) secretome has pleiotropic effects which underpin their therapeutic potential. hMSC serum-free conditioned media (SFCM) has been determined to contain a variety of cytokines with roles in regeneration and suppression of inflammation. Physiological oxygen (physoxia) has been demonstrated to impact upon a number of facets of hMSC biology and we hypothesized that the secretome would be similarly modified. We tested a range of oxygen conditions; 21% O2 (air oxygen (AO)), 2% O2 (intermittent hypoxia (IH)) and 2% O2 Workstation (physoxia (P)) to evaluate their effect on hMSC secretome profiles. Total protein content of secretome was upregulated in IH and P (>3 fold vs AO) and IH (>1 fold vs P). Focused cytokine profiling indicated global upregulation in IH of all 31 biomolecules tested in comparison to AO and P with basic-nerve growth factor (bNGF) and granulocyte colony-stimulating factor (GCSF) (>3 fold vs AO) and bNGF and Rantes (>3 fold vs P) of note. Similarly, upregulation of interferon gamma-induced protein 10 (IP10) was noted in P (>3 fold vs AO). Interleukin-2 (IL2) and Rantes (in AO and P) and adiponectin, IL17a, and epidermal growth factor (EGF) (in AO only) were entirely absent or below detection limits. Quantitative analysis validated the pattern of IH-induced upregulation in vascular endothelial growth factor (VEGF), placental growth factor-1 (PIGF1), Tumor necrosis factor alpha (TNFa), IL2, IL4, and IL10 when compared to AO and P. In summary, modulation of environmental oxygen alters both secretome concentration and composition. This consideration will likely impact on delivering improved mechanistic understanding and potency effects of hMSC-based therapeutics.

scholarly journals Novel human Ab against vascular endothelial growth factor receptor 2 shows therapeutic potential for leukemia and prostate cancer

2019 ◽  
Vol 110 (12) ◽  
pp. 3773-3787 ◽  
Author(s):  
Ruei‐Min Lu ◽  
Chiung‐Yi Chiu ◽  
I‐Ju Liu ◽  
Yu‐Ling Chang ◽  
Yaw‐Jen Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Therapeutic Potential ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

scholarly journals Relaxin Induces Rapid Dilation of Rodent Small Renal and Human Subcutaneous Arteries via PI3 Kinase and Nitric Oxide

Endocrinology ◽  
2011 ◽  
Vol 152 (7) ◽  
pp. 2786-2796 ◽  
Author(s):  
Jonathan T. McGuane ◽  
Julianna E. Debrah ◽  
Laura Sautina ◽  
Yagna P. R. Jarajapu ◽  
Jacqueline Novak ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Therapeutic Potential ◽  
Growth Factor Receptor ◽  
Peptide Hormone ◽  
Mesenteric Arteries ◽  
No Production ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

The peptide hormone relaxin is a potent vasodilator with therapeutic potential in diseases complicated by vasoconstriction, including heart failure. However, the molecular mediators and magnitude of vasodilation may vary according to duration of exposure and artery type. The objective of these studies was to determine mechanisms of rapid (within minutes) relaxin-induced vasodilation and to examine whether relaxin dilates arteries from different animal species and vascular beds. Rat and mouse small renal, rat mesenteric, and human sc arteries were isolated, mounted in a pressure arteriograph, and treated with recombinant human relaxin (rhRLX; 1–100 ng/ml) after preconstriction with phenylephrine. Rat and mouse small renal as well as human sc arteries dilated in response to rhRLX, whereas rat mesenteric arteries did not. Endothelial removal or pretreatment with l-NG-monomethyl arginine (L-NMMA) abolished rapid relaxin-induced vasodilation; phosphatidylinositol-3-kinase (PI3K) inhibitors also prevented it. In cultured human endothelial cells, rhRLX stimulated nitric oxide (assessed using 4-amino-5-methylamino-2′7′-difluorofluorescein) as well as Akt and endothelial NO synthase (eNOS) phosphorylation by Western blotting but not increases in intracellular calcium (evaluated by fura-2). NO production was attenuated by inhibition of Gαi/o and Akt (using pertussis toxin and the allosteric inhibitor MK-2206, respectively), PI3K, and NOS. Finally, the dilatory effect of rhRLX in rat small renal arteries was unexpectedly potentiated, rather than inhibited, by pretreatment with the vascular endothelial growth factor receptor inhibitor SU5416. We conclude that relaxin rapidly dilates select arteries across a range of species. The mechanism appears to involve endothelial Gαi/o protein coupling to PI3K, Akt, and eNOS but not vascular endothelial growth factor receptor transactivation or increased calcium.

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