Erythropoietin accelerates the revascularization of transplanted pancreatic islets

Menger, Maximilian M.; Nalbach, Lisa; Roma, Letícia Prates; Körbel, Christina; Wrublewsky, Selina; Glanemann, Matthias; Laschke, Matthias W.; Menger, Michael D.; Ampofo, Emmanuel

doi:10.1111/bph.14925

Cited by 10 publications

(14 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Unfortunately, both the DPO low-dose and the DPO high-dose treatment failed to accelerate the process of revascularization, as indicated by a similar functional capillary density between the 3 experimental groups throughout the observation period. In fact, the DPO low-dose treatment showed an even lower angiogenic response when compared to the EPO treatment performed in our previous study [ 30 ]. Furthermore, the relative size of the vascular network and the endocrine revascularization did not differ between the three experimental groups.…”

Section: Discussionmentioning

confidence: 54%

“…We have recently shown that EPO is a promising compound to accelerate the revascularization process of transplanted pancreatic islets. However, the pro-angiogenic effect was predominant, when EPO was administrated prior islet transplantation [ 30 ]. This pretreatment might not be possible to transfer in a clinical setting, as the transplantation process is a swift procedure with little time between receiving the donor organ and the transplantation itself.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, an adequate pretreatment of patients with EPO might not be possible under clinical conditions. EPO treatment starting on the day of transplantation, however, showed only little effect in improving revascularization of freely transplanted islets [ 4 ]. This reduced effect might be due to the fact that the generation of a suitable plasma level of EPO requires several days.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Darbepoetin-α increases the blood volume flow in transplanted pancreatic islets in mice

et al. 2020

Self Cite

View full text Add to dashboard Cite

Aims The minimal-invasive transplantation of pancreatic islets is a promising approach to treat diabetes mellitus type 1. However, islet transplantation is still hampered by the insufficient process of graft revascularization, leading to a poor clinical outcome. Accordingly, the identification of novel compounds, which accelerate and improve the revascularization of transplanted islets, is of great clinical interest. Previous studies have shown that darbepoetin (DPO)-α, a long lasting analogue of erythropoietin, is capable of promoting angiogenesis. Hence, we investigated in this study whether DPO improves the revascularization of transplanted islets. Methods Islets were isolated from green fluorescent protein-positive FVB/N donor mice and transplanted into dorsal skinfold chambers of FVB/N wild-type animals, which were treated with DPO low dose (2.5 µg/kg), DPO high dose (10 µg/kg) or vehicle (control). The revascularization was assessed by repetitive intravital fluorescence microscopy over an observation period of 14 days. Subsequently, the cellular composition of the grafts was analyzed by immunohistochemistry. Results The present study shows that neither low- nor high-dose DPO treatment accelerates the revascularization of free pancreatic islet grafts. However, high-dose DPO treatment increased the blood volume flow of the transplanted islet. Conclusions These findings demonstrated that DPO treatment does not affect the revascularization of transplanted islets. However, the glycoprotein increases the blood volume flow of the grafts, which results in an improved microvascular function and may facilitate successful transplantation.

show abstract

Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Darbepoetin-α increases the blood volume flow in transplanted pancreatic islets in mice

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Mice with a non‐fasting blood glucose level ≥ 350 mg/dl served as recipients for islet transplantation (Sakata et al , 2012). Four hundred FI, 300 FI, 250 FI, 200 FI, and 250 PI + MVF were injected under the kidney capsule of diabetic mice using a 10 µl Hamilton syringe, as described previously in detail (Menger et al , 2020). Blood glucose levels and body weight were monitored over the entire observation period of 28 days twice a week.…”

Section: Methodsmentioning

confidence: 99%

“…Significant research efforts have been conducted to promote the revascularization and, thus, to improve nutrient and oxygen supply of grafted islets during the first post‐transplantational days (Song et al , 2019; Menger et al , 2020). A promising strategy to achieve this is the prevascularization of the transplantation site, as already described for subcutaneous tissue by means of a catheter technique (Pepper et al , 2015).…”

Section: Introductionmentioning

confidence: 99%

Improvement of islet transplantation by the fusion of islet cells with functional blood vessels

et al. 2020

Self Cite

View full text Add to dashboard Cite

Pancreatic islet transplantation still represents a promising therapeutic strategy for curative treatment of type 1 diabetes mellitus. However, a limited number of organ donors and insufficient vascularization with islet engraftment failure restrict the successful transfer of this approach into clinical practice. To overcome these problems, we herein introduce a novel strategy for the generation of prevascularized islet organoids by the fusion of pancreatic islet cells with functional native microvessels. These insulin-secreting organoids exhibit a significantly higher angiogenic activity compared to freshly isolated islets, cultured islets, and non-prevascularized islet organoids. This is caused by paracrine signaling between the b-cells and the microvessels, mediated by insulin binding to its corresponding receptor on endothelial cells. In vivo, the prevascularized islet organoids are rapidly blood-perfused after transplantation by the interconnection of their autochthonous microvasculature with surrounding blood vessels. As a consequence, a lower number of islet grafts are required to restore normoglycemia in diabetic mice. Thus, prevascularized islet organoids may be used to improve the success rates of clinical islet transplantation.

show abstract

Erythropoietin exposure of isolated pancreatic islets accelerates their revascularization after transplantation

et al. 2021

Self Cite

View full text Add to dashboard Cite

Aims The exposure of isolated pancreatic islets to pro-angiogenic factors prior to their transplantation represents a promising strategy to accelerate the revascularization of the grafts. It has been shown that erythropoietin (EPO), a glycoprotein regulating erythropoiesis, also induces angiogenesis. Therefore, we hypothesized that EPO exposure of isolated islets improves their posttransplant revascularization. Methods Flow cytometric, immunohistochemical and quantitative real-time (qRT)-PCR analyses were performed to study the effect of EPO on the viability, cellular composition and gene expression of isolated islets. Moreover, islets expressing a mitochondrial or cytosolic H2O2 sensor were used to determine reactive oxygen species (ROS) levels. The dorsal skinfold chamber model in combination with intravital fluorescence microscopy was used to analyze the revascularization of transplanted islets. Results We found that the exposure of isolated islets to EPO (3 units/mL) for 24 h does not affect the viability and the production of ROS when compared to vehicle-treated and freshly isolated islets. However, the exposure of islets to EPO increased the number of CD31-positive cells and enhanced the gene expression of insulin and vascular endothelial growth factor (VEGF)-A. The revascularization of the EPO-cultivated islets was accelerated within the initial phase after transplantation when compared to both controls. Conclusion These findings indicate that the exposure of isolated islets to EPO may be a promising approach to improve clinical islet transplantation.

show abstract

Erythropoietin accelerates the revascularization of transplanted pancreatic islets

Cited by 10 publications

References 61 publications

Darbepoetin-α increases the blood volume flow in transplanted pancreatic islets in mice

Darbepoetin-α increases the blood volume flow in transplanted pancreatic islets in mice

Improvement of islet transplantation by the fusion of islet cells with functional blood vessels

Erythropoietin exposure of isolated pancreatic islets accelerates their revascularization after transplantation

Contact Info

Product

Resources

About