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Vascularized and functional liver devided from human induced pluripotent stem cells by recapitulating organogenesis
Abstract
Due to a severe donor shortage crisis, over 100,000 patients waiting for transplants per year die of end-stage organ failure in the United States alone. Laboratory-grown functional organs derived from pluripotent stem cells, such as induced pluripotent stem cells (iPSCs), may be one promising solution to this organ shortage. However, it has been considered impractical to recapitulate in stem cell cultures the spatiotemporal control of the multicellular interactions that occur during embryogenesis to generate a complex and vascularized organ, such as the liver. Recently, we reported that a three-dimensional iPSC-derived rudimentary organ (liver bud) could be grown from mixed human liver progenitors in a specific three-dimensional culture by mimicking early organogenic cellular interactions. The transplantation of this iPSC-derived liver bud was effective in rescuing lethal liver failure, a proof of principle that highlights the enormous therapeutic potential of this approach (i.e., in vitro-grown organ-bud transplantation). The present manuscript provides an overview of this new regenerative paradigm for future clinical application.
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Generation of functional and vascularized organs from human induced pluripotent stem cells (iPSCPSCPSCs) will facilitate our understanding of human developmental biology and disease modeling, hopefully offering a drug-screening platform and providing novel therapies against end-stage organ failure. Here we describe a protocol for the in vitro generation of a 3D liver bud from human iPSCPSCPSC cultures and the monitoring of further hepatic maturation after transplantation at various ectopic sites. iPSCPSCPSC-derived specified hepatic cells are dissociated and suspended with endothelial cells and mesenchymal stem cells. These mixed cells
are then plated onto a presolidified matrix, and they form a 3D spherical tissue mass termed a liver bud (iPSCPSCPSC-LB) in 1–2 d. To facilitate additional maturation, 4-d-old iPSCPSCPSC-LBs are transplanted in the immunodeficient mouse. Live imaging has identified functional blood perfusion into the preformed human vascular networks. Functional analyses show the appearance of multiple hepatic functions in a chronological manner in vivo.
Significance
Human pluripotent stem cells (hPSCs) can be produced from any person and have the potential to differentiate into any cell type in the body. This study focuses on the generation of insulin-expressing cells from hPSCs and compares their gene expression, as assayed by transcriptional gene products, to that of insulin-expressing β cells from human fetal and adult samples. We employ a new method to isolate and profile insulin-expressing cells and conclude that several different hPSC lines generate very similar insulin-expressing cells, cells whose transcripts resemble fetal rather than adult β cells. This study advances the possibility of directing the differentiation of stem cells into functional β cells by comparing and cataloging differences between hPSC-derived insulin-expressing cells and human β cells.
The success of clinical transplantation as a therapy for end-stage organ failure is limited by the availability of suitable organs for transplant. This article discusses continued efforts by the transplant community to collaboratively improve the organ supply. There were 7593 deceased organ donors in 2005. This represents an all-time high and a 6% increase over 2004. Increases were noted in deceased organ donation of all types of organs; notable is the increase in lung donation, which occurred in 17% of all deceased donors. The percentage of deceased donations that occurred following cardiac death has also reached a new high at 7%. The number of living donors decreased by 2%, from 7003 in 2004 to 6895 in 2005. This article discusses the continued efforts of the Organ Donation Breakthrough Collaborative and the Organ Transplantation Breakthrough Collaborative to support organ recovery and use and to encourage the expectation that for every deceased donor, all organs will be placed and transplanted.