December 5, 2023


Biochem. improved post-transplant engraftment. Therapeutically, fulminant diabetic mice were more efficiently treated by a vascularized islet transplant compared with the conventional approach. Given the general limitations of post-transplant vascularization associated with 3D tissue-based therapy, our approach offers a promising means of enhancing efficacy in the context of therapeutic tissue transplantation. In Brief Takahashi et al. report on generating vascularized islet tissue from humans and mice. After transplantation, vascularized islets significantly improve survival of diabetic mice, demonstrating the quick normalization of blood glucose compared with conventional islet transplantation. Graphical Abstract INTRODUCTION Tissue-based therapies are gathering clinical momentum as Darunavir Ethanolate (Prezista) Slc2a3 next-generation treatments for organ dysfunction, driven by the recent success of islet transplantation. Additionally, technological innovations such as stem cell-based tissue engineering approaches highlighted tremendous therapeutic potential; however, future clinical applications of such tissue-based approaches face a critical challenge related to effective transplantation strategies that make sure efficient engraftment through the timely development of vascular networks. A well-studied clinical example of tissue-based therapy is usually islet transplantation, which has successfully been used to promote insulin independence in patients with severe type 1 diabetes (Shapiro et al., 2000). However, transplanted islets have a substantially low engraftment rate because the loss of the vasculature during the isolation process induces necrosis, making Darunavir Ethanolate (Prezista) it difficult to maximize the treatment efficacy of the transplant. Therefore, the rapid establishment of vascular networks is extremely important for the proper engraftment and function of transplanted islets. Recent attempts to improve post-transplant engraftment have included prevascularized niche construction (Moore et al., 2015), co-transplantation (Coppens et al., 2013; Kang et al., 2012; Oh et al., 2013), and tissue engineering (Moore et al., 2015; Perez-Basterrechea et al., 2013). Nevertheless, transplant vascularization generally takes at least 7 days, and the rapid introduction of vasculature into a transplanted tissue remains a considerable challenge. Recently, we have developed a dynamic self-condensation approach to develop tissue organoids from dissociated organ progenitor cells in the presence of stromal vascular and mesenchymal progenitors (Takebe et al., 2014). Early success was reported using self-organizing liver buds to model early hepatogenesis, Darunavir Ethanolate (Prezista) demonstrating the therapeutic potential of this strategy for treating lethal liver diseases (Takebe et al., 2013). Recent work adapting this approach to multiple organ-derived dissociated cells exhibited the potential to generate diverse organ rudiments (organ buds) in culture (Takebe et al., 2015). Although this strategy enabled rapid blood vessel induction in tissue organoids generated from single cells in suspension, whether tissue fragments such as islet can also be adapted to follow this self-condensation theory remains unclear. Here, we first exhibited the adaptability of our self-condensation culture using tissue fragments from diverse organ systems, enabling endothelialized 3D tissue formation. Further studies of pancreatic islets from both humans and mice Darunavir Ethanolate (Prezista) revealed that introducing an endothelial network to the culture not merely facilitates vascularization, but also improves tissue viability and functionality (insulin secretion capacity) even prior to blood perfusion. Remarkably, the resulting Darunavir Ethanolate (Prezista) endothelialized islet (hereafter referred to as vascularized islet) transplants exhibited significantly improved therapeutic potential in a fulminant diabetes model through improved post-transplant engraftment. Our approach highlights the promise of using self-condensing cultures for tissue vascularization in future clinical transplantation studies. RESULTS Successful Self-Condensation into a 3D Vascularized Tissue from Diverse Tissue Fragments Previously, we developed a self-condensation method for generating vascularized tissues from dissociated cell suspensions via co-culturing with human mesenchymal stem cells (MSCs) on soft substrate. Here, we adapted this approach to generate vascularized tissue from isolated adult tissue fragments or human induced pluripotent stem cell (iPSC)-derived tissues (Physique 1A). The results showed that applying this self-condensation approach to other tissue fragments isolated from adult animals or human pluripotent stem cell-derived tissues led to the successful formation of endothelialized and condensed tissues, the diameter of which is applicable even up to 1 1,000 m (Physique 1B; Video S1). Once human umbilical cord-derived endothelial cells (HUVECs) are included, generated tissues quickly form a functional vasculature score ranging.