Generation of interspecies limited chimeric nephrons using a conditional nephron progenitor cell replacement system

S. Yamanaka,B. S. Kim,S. Fukunaga,T. Fujimoto,T. Yokoo,S. Tajiri,H. J. Okano,K. Matsumoto

doi:10.1038/s41467-017-01922-5

S. Yamanaka, B. S. Kim + Show 6 more

Open Access

https://doi.org/10.1038/s41467-017-01922-5

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Abstract

Animal fetuses and embryos may have applications in the generation of human organs. Progenitor cells may be an appropriate cell source for regenerative organs because of their safety and availability. However, regenerative organs derived from exogenous lineage progenitors in developing animal fetuses have not yet been obtained. Here, we established a combination system through which donor cells could be precisely injected into the nephrogenic zone and native nephron progenitor cells (NPCs) could be eliminated in a time- and tissue-specific manner. We successfully achieved removal of Six2+ NPCs within the nephrogenic niche and complete replacement of transplanted NPCs with donor cells. These NPCs developed into mature glomeruli and renal tubules, and blood flow was observed following transplantation in vivo. Furthermore, this artificial nephron could be obtained using NPCs from different species. Thus, this technique enables in vivo differentiation from progenitor cells into nephrons, providing insights into nephrogenesis and organ regeneration.

Highlights

Animal fetuses and embryos may have applications in the generation of human organs
To evaluate whether isolated nephron progenitor cells (NPCs) could be integrated into the CM region, which is the origin of nephron development, we attempted transplantation into the nephrogenic zone of the MN at the same embryonic stage
In this study, we used a combination of a specified cell injection method and a drug-induced cell elimination system to exchange native NPCs with exogenous NPCs and generate regenerative nephrons from transplanted NPCs (Fig. 5e and Supplementary Movies 3–6)

Summary

Introduction

Animal fetuses and embryos may have applications in the generation of human organs. Progenitor cells may be an appropriate cell source for regenerative organs because of their safety and availability. We have developed a strategy for applying multipotent stem cells at the niche of organogenesis[2,3,4,5,6,7,8] This strategy involves transplantation of human cells into the area of nephrogenesis in a fetus of a different animal species, thereby generating human cellderived kidneys[2]. Many researchers have attempted to explore interspecies chimeras or chimeric organs using embryos and fetuses of different animals[10] Using such technology, attempts to regenerate solid organs, such as pancreases and kidneys, in xenoanimals have recently been made using blastocyst complementation, in which embryonic stem (ES) cells or induced pluripotent (iPS) cells are injected into blastocysts lacking key molecules to generate the organ of interest[11, 12]. We hypothesized that it would be optimal to transplant progenitor cells into a fetus during this specific period and assumed that this method of exploiting limited chimeras may prove useful for organ regeneration

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