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Background Peripheral artery disease is an ischemic vascular disease caused by the blockage of blood vessels supplying blood to the lower extremities. Mesenchymal stem cells (MSCs) and endothelial colony-forming cells (ECFCs) have been reported to alleviate peripheral artery disease by forming new blood vessels. However, the clinical application of MSCs and ECFCs has been impeded by their poor in vivo engraftment after cell transplantation. To augment in vivo engraftment of transplanted MSCs and ECFCs, we investigated the effects of hybrid cell spheroids, which mimic a tissue-like environment, on the therapeutic efficacy and survival of transplanted cells. Methods The in vivo survival and angiogenic activities of the spheroids or cell suspension composed of MSCs and ECFCs were measured in a murine hindlimb ischemia model and Matrigel plug assay. In the hindlimb ischemia model, the hybrid spheroids showed enhanced therapeutic effects compared with the control groups, such as adherent cultured cells or spheroids containing either MSCs or ECFCs. Results Spheroids from MSCs, but not from ECFCs, exhibited prolonged in vivo survival compared with adherent cultured cells, whereas hybrid spheroids composed of MSCs and ECFCs substantially increased the survival of ECFCs. Moreover, single spheroids of either MSCs or ECFCs secreted greater levels of pro-angiogenic factors than adherent cultured cells, and the hybrid spheroids of MSCs and ECFCs promoted the secretion of several pro-angiogenic factors, such as angiopoietin-2 and platelet-derived growth factor. Conclusion These results suggest that hybrid spheroids containing MSCs can serve as carriers for cell transplantation of ECFCs which have poor in vivo engraftment efficiency.
Background Peripheral artery disease is an ischemic vascular disease caused by the blockage of blood vessels supplying blood to the lower extremities. Mesenchymal stem cells (MSCs) and endothelial colony-forming cells (ECFCs) have been reported to alleviate peripheral artery disease by forming new blood vessels. However, the clinical application of MSCs and ECFCs has been impeded by their poor in vivo engraftment after cell transplantation. To augment in vivo engraftment of transplanted MSCs and ECFCs, we investigated the effects of hybrid cell spheroids, which mimic a tissue-like environment, on the therapeutic efficacy and survival of transplanted cells. Methods The in vivo survival and angiogenic activities of the spheroids or cell suspension composed of MSCs and ECFCs were measured in a murine hindlimb ischemia model and Matrigel plug assay. In the hindlimb ischemia model, the hybrid spheroids showed enhanced therapeutic effects compared with the control groups, such as adherent cultured cells or spheroids containing either MSCs or ECFCs. Results Spheroids from MSCs, but not from ECFCs, exhibited prolonged in vivo survival compared with adherent cultured cells, whereas hybrid spheroids composed of MSCs and ECFCs substantially increased the survival of ECFCs. Moreover, single spheroids of either MSCs or ECFCs secreted greater levels of pro-angiogenic factors than adherent cultured cells, and the hybrid spheroids of MSCs and ECFCs promoted the secretion of several pro-angiogenic factors, such as angiopoietin-2 and platelet-derived growth factor. Conclusion These results suggest that hybrid spheroids containing MSCs can serve as carriers for cell transplantation of ECFCs which have poor in vivo engraftment efficiency.
Background Adipose tissue-derived microvascular fragments are functional vessel segments derived from arterioles, capillaries, and veins. Microvascular fragments can be used as vascularization units in regenerative medicine and tissue engineering containing microvascular networks. However, the in vivo therapeutic and vascularization properties of human microvascular fragments have not been investigated. Methods In this study, we isolated microvascular fragments, stromal vascular fractions, and mesenchymal stem cells from human lipoaspirate and studied their therapeutic efficacy and in vivo vasculogenic activity in a murine model of hindlimb ischemia. In addition, in vivo angiogenic activity and engraftment of microvascular fragments into blood vessels were measured using Matrigel plug assay. Results Both microvascular fragments and stromal vascular fractions contain not only mesenchymal stem cells but also endothelial progenitor cells. In a Matrigel plug assay, microvascular fragments increased the number of blood vessels containing red blood cells more than mesenchymal stem cells and stromal vascular fractions did. The engraftment of the microvascular fragments transplanted in blood vessels within the Matrigel plug significantly increased compared to the engraftment of mesenchymal stem cells and stromal vascular fractions. Moreover, intramuscular injection of microvascular fragments markedly increased blood flow in the ischemic hindlimbs and alleviated tissue necrosis compared to that of mesenchymal stem cells or stromal vascular fractions. Furthermore, transplanted microvascular fragments formed new blood vessels in ischemic limbs. Conclusions These results suggest that microvascular fragments show improved engraftment efficiency and vasculogenic activity in vivo and are highly useful for treating ischemic diseases and in tissue engineering. Graphical Abstract Adipose tissue-derived microvascular fragments are vascularization units in regenerative medicine and tissue engineering containing microvascular networks. Intramuscular injection of microvascular fragments markedly increased blood flow in the ischemic hindlimbs and alleviated tissue necrosis. The present study suggests that microvascular fragments show improved engraftment efficiency and vasculogenic activity in vivo and are highly useful for treating ischemic diseases and in tissue engineering.
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