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Bud-ding New Strategy for Organ Formation Shows Success!

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Review of “Vascularized and Complex Organ Buds from Diverse Tissues via Mesenchymal Cell-Driven Condensation” from Cell Stem Cell by Stuart P. Atkinson

Three dimensional organoid production has been one of the “hot topics” in regenerative medicine of the past year, and this strategy is making some headway into solving the problem of donor organ shortages. Researchers from the laboratories of Hiroshi Y. Yoshikawa and Hideki Taniguchi had previously demonstrated the in vitro formation of a 3D transplantable liver “organ bud” from human induced pluripotent stem cells (iPSCs) co-cultured with mesenchymal and endothelial progenitors, and allows for the growth of a small vascularized and functional organ [1-3]. Now, in a new study in Cell Stem Cell, the group have begun to delineate the mechanisms controlling organ bud formation, and from these findings they have been able to describe a general methodology for the formation of large vascularized, complex organ buds from diverse organs using specific stem cell combinations [4].

Initial imaging analysis of fluorescently labelled human iPSC-derived hepatic endoderm cells, umbilical cord-derived endothelial cells (HUVECs), and mesenchymal stem cells (MSCs) co-cultured in a solidified matrix gel to promote 3D growth found that the different cells collectively and automatically “condensed” into a multicellular central unit. Detailed investigations demonstrated that the formation of stress fibers and cell-cell junctions created the force necessary for the condensation process, all mediated by MSCs through the actomyosin cytoskeletal axis. Further analysis of the 3D culture matrix elasticity found that while soft matrices led to larger condensates, the stiffer matrices allowed for much smaller condensate production, although overall the Matrigel matrix functioned the most efficiently. These different mechanisms all allowed for the process of self-assembly of vascularized liver organ buds involving spatial rearrangements via self-organization.

Following the delineation of some of the basic principles behind bud formation, the researchers then whether they could extend this strategy beyond the liver, and create other organ buds using tissue specific cell types. Indeed they observed dynamic condensation when using multiple cells or tissue fragments containing stem/progenitor cells isolated from adult or fetal intestine, lung, heart, kidney, and brain. In vitro 3D bud formation followed by cranial transplantation into mice also found that the inclusion of endothelial cells always allowed for a much more rapid perfusion with the host circulation, altogether suggesting that their new strategy functioned extremely well across a number of tissue types.

Functional assessment of these organ buds first used murine -cells co-cultured with HUVECs and MSCs, which formed a pancreatic condensate similar to the liver organ bud. This stable self-organized pancreatic bud connected to the host circulation after transplant, and went on to developed islet-like structures with functional microvascular networks. Excitingly, when transplanted into a mouse model of diabetes, the pancreatic bud allowed for the rapid normalization of body weight and blood glucose levels. The researchers also demonstrated the adaptation of this strategy to kidney bud formation using embryonic kidney cells, and resulted in the formation of integrated glomerular-like tissues after transplantation. This suggests that embryonic cells may be more useful than adult-derived cells in some cases, and that the strategy described here may promote any intrinsic self-organizing capacity held by embryonic cells.

This exciting new strategy promises a scalable and flexible strategy for the formation of vascularized and functional organ buds of a useful size, all via the condensation of specific cells from desired multiple cell/tissue types. So where next? The authors note that the formation of each different organ bud type may require some fine tuning to optimize tissue self-organization, and further addition of neural cell types may be necessary, but this research may soon provide exciting model systems for the study of basic biology and pathology as well as providing appropriate replacement tissues for the treatment of many patients with no other viable options.

References

  1. Takebe T, Sekine K, Suzuki Y, et al. Self-organization of human hepatic organoid by recapitulating organogenesis in vitro. Transplantation proceedings 2012;44:1018-1020.
  2. Takebe T, Zhang RR, Koike H, et al. Generation of a vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature protocols 2014;9:396-409.
  3. Takebe T, Sekine K, Enomura M, et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 2013;499:481-484.
  4. Takebe T, Enomura M, Yoshizawa E, et al. Vascularized and Complex Organ Buds from Diverse Tissues via Mesenchymal Cell-Driven Condensation. Cell Stem Cell 2015.