Co-transplantation of pancreatic islets and microvascular fragments effectively restores normoglycemia in diabetic mice

Abstract

Insufficient revascularization of pancreatic islets is one of the major obstacles impairing the success of islet transplantation. To overcome this problem, we introduce in the present study a straightforward strategy to accelerate the engraftment of isolated islets. For this purpose, we co-transplanted 250 islets and 20,000 adipose tissue-derived microvascular fragments (MVF) from donor mice under the kidney capsule as well as 500 or 1000 islets with 40,000 MVF into the subcutaneous space of diabetic mice. We found that the co-transplantation of islets and MVF markedly accelerates the restoration of normoglycemia in diabetic recipients compared with the transplantation of islets alone. In fact, the transplantation of 250 islets with 20,000 MVF under the kidney capsule reversed diabetes in 88% of mice and the subcutaneous transplantation of 500 or 1000 islets with 40,000 MVF restored normoglycemia in 100% of mice. Moreover, diabetic mice receiving islets and MVF exhibited plasma insulin levels similar to nondiabetic control animals. Additional immunohistochemical analyses of the grafts revealed a significantly higher number of islet cells and microvessels in the co-transplantation groups. These findings demonstrate that the co-transplantation of islets and MVF is a promising strategy to improve the success rates of islet transplantation, which could be easily implemented into future clinical practice.

Biomaterial-assisted strategies to improve islet graft revascularization and transplant outcomes

“…97 Notably, they demonstrate rapid reassembly into functional microvascular networks and establish connections with the host microvasculature after being transplanted into tissue defects. 98 In a study by Wrublewsky et al, 99 250 islet cells and 20 000 MVFs from adipose tissue were transplanted into kidney capsules, while 500 islet cells and 40 000 MVF were transplanted into the subcutaneous space of diabetic mice (Fig. 7).…”

“…Additionally, the glucose metabolism of diabetic mice improved following co-transplantation. 99 This strategy not only achieves favorable efficacy but also circumvents the need for complex and time-consuming tissue engineering approaches, making it more suitable for future clinical applications.…”

“…In a study by Wrublewsky et al , 99 250 islet cells and 20 000 MVFs from adipose tissue were transplanted into kidney capsules, while 500 islet cells and 40 000 MVF were transplanted into the subcutaneous space of diabetic mice (Fig. 7).…”

Isolated Fragments of Intact Microvessels: Tissue Vascularization, Modeling, and Therapeutics

“…Over the years, iMVs have been used in countless applications, such as for studying angiogenesis-tissue biomechanics [36][37][38], stromal cell and vascular precursor dynamics [39,40], postangiogenesis microvascular maturation and patterning [41], imaging methods to assess neovascular behavior [42], whole-tissue modeling [43,44], and for prevascularization of tissue and cellular grafts [27,[45][46][47][48][49][50][51]. Intact microvessels have also served as a platform for evaluating the effect of angiogenic factors and agents [52][53][54][55][56][57][58], evaluating microvascular instability [59,60], assessing MMP-related angiogenic activity [52], and studying the dynamic role of the extracellular matrix during angiogenesis [37,42].…”

“…The iMV and iPSCcardiomyocyte co-injection was able to increase vascular density and restore lost ventricular function, whereas cells alone were unable to do so [49]. Similarly, iMVs have been co-engrafted with pancreatic islets to improve graft viability and performance [46,47]. Wrublewsky et al co-delivered islets with iMVs, restoring normoglycemia and normalizing plasma insulin levels in 88% of diabetic mice within 28 days, compared with 12.5% in diabetic mice that had received islets alone.…”