Vascularized and functional human liver from an iPSC-derived organ bud transplant

Abstract

A critical shortage of donor organs for treating end-stage organ failure highlights the urgent need for generating organs from human induced pluripotent stem cells (iPSCs). Despite many reports describing functional cell differentiation, no studies have succeeded in generating a three-dimensional vascularized organ such as liver. Here we show the generation of vascularized and functional human liver from human iPSCs by transplantation of liver buds created in vitro (iPSC-LBs). Specified hepatic cells (immature endodermal cells destined to track the hepatic cell fate) self-organized into three-dimensional iPSC-LBs by recapitulating organogenetic interactions between endothelial and mesenchymal cells. Immunostaining and gene-expression analyses revealed a resemblance between in vitro grown iPSC-LBs and in vivo liver buds. Human vasculatures in iPSC-LB transplants became functional by connecting to the host vessels within 48 hours. The formation of functional vasculatures stimulated the maturation of iPSC-LBs into tissue resembling the adult liver. Highly metabolic iPSC-derived tissue performed liver-specific functions such as protein production and human-specific drug metabolism without recipient liver replacement. Furthermore, mesenteric transplantation of iPSC-LBs rescued the drug-induced lethal liver failure model. To our knowledge, this is the first report demonstrating the generation of a functional human organ from pluripotent stem cells. Although efforts must ensue to translate these techniques to treatments for patients, this proof-of-concept demonstration of organ-bud transplantation provides a promising new approach to study regenerative medicine.

Monocrotophos in Gandaman village: India school lunch deaths and need for improved toxicity testing

“…Three-dimensional culture techniques (Hoelting et al 2013) have enabled the generation of PSC-derived organoids (e.g., Preynat-Seauve et al 2009), allowing putative toxic compounds to be tested on tissues rather than on isolated cells. Finally, the use of PSCs to generate mice with humanized organs (e.g., Takebe et al 2013) provides new opportunities to represent physiological complexity. Collectively, we believe these constitute next-generation toxicity platforms.…”

Translational potential of human brain organoids

“…This landmark paper established a novel experimental paradigm for generating tissue organoids. Subsequent studies worldwide confirmed the generalizability of such approach to human stem cells, and produced organoids of a variety of organ types including colon,11 intestine,12 prostate,13, 14 fallopian tube,15 stomach,16 liver,17, 18 kidney,19 lung,20 and brain 8…”

Modeling infectious diseases and host-microbe interactions in gastrointestinal organoids

“…The virus preferentially infected and replicated in neural progenitors, induced cell death and decreased proliferation, leading to reduced neuronal cell layers and thus phenocopying the microencephaly caused by the virus in human fetuses (Dang et al, 2016;Garcez et al, 2016;Tang et al, 2016). Other organoids such as lung (Dye et al, 2015;Huang et al, 2013), liver Takebe et al, 2013), kidney (Takasato et al, 2015) and fallopian tube organoids (Kessler et al, 2015) may represent ideal models for infections of the respective tissues, such as respiratory virus, malaria parasite, biofilm-producing E. coli or Chlamydia infection, respectively. Future studies will use the unique features of organoids, such as the presence of specific cell types, to better understand infectious and inflammatory diseases.…”