Developmentally inspired kidney tissues derived from stem cells hold promise for future renal replacement tissue, but clinical translation is limited by variability in outcomes, absence of cell types, lack of functional maturity and implausible scalability.
Developmentally inspired kidney tissues derived from stem cells hold promise for future renal replacement tissue, but clinical translation is limited by variability in outcomes, absence of cell types, lack of functional maturity and implausible scalability.
Overcoming these may benefit from tissue engineering strategies that leverage processes for tissue construction that the embryonic kidney uses to achieve its diverse and parallelized functions. We present a ‘developmental engineering’ strategy in which spatial and temporal cues inspired by in vivo development guide multiscale structure formation in vitro. We highlight emerging tools in synthetic biology, spatial patterning and control over tissue microenvironments that can set initial and boundary conditions to instigate and guide the development of a desired ‘motif’. We then present a vision for scalable developmental engineering by guiding and daisy-chaining tissue motifs, bridging discontinuities in self-organization via direct assembly. Although we articulate a blueprint for developmental engineering of translationally viable renal replacement tissues, the strategy is also applicable to other solid organs.Fig. 1: Metanephric kidney development parallelizes nephron-forming stem cell niches. Fig. 2: Developmental engineering strategy: setting initial and boundary conditions that guide self-organization within a target motif.Fig. 4: Developmental engineering of the NP and UB lineages.US Food and Drug Administration. FDA announces plan to phase out animal testing requirement for monoclonal antibodies and other drugsVanslambrouck, J. M., Tan, K. S., Mah, S. & Little, M. H. Generation of proximal tubule-enhanced kidney organoids from human pluripotent stem cells.Shi, M., Fu, P., Bonventre, J. V. & McCracken, K. W. Directed differentiation of ureteric bud and collecting duct organoids from human pluripotent stem cells.Pfeifer, C. R., Shyer, A. E. & Rodrigues, A. R. 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Z. & Hughes, A. J. Measurement of adhesion and traction of cells at high yield reveals an energetic ratchet operating during nephron condensation.Toda, S., Blauch, L. R., Tang, S. K. Y., Morsut, L. & Lim, W. A. Programming self-organizing multicellular structures with synthetic cell–cell signaling.Georgas, K. et al. Analysis of early nephron patterning reveals a role for distal RV proliferation in fusion to the ureteric tip via a cap mesenchyme-derived connecting segment.Fausto, C. C. et al. Defining and controlling axial nephron patterning in human kidney organoids with synthetic Wnt-secreting organizers. Preprint atVanslambrouck, J. M. et al. Enhanced metanephric specification to functional proximal tubule enables toxicity screening and infectious disease modelling in kidney organoids.Martyn, I., Kanno, T. Y., Ruzo, A., Siggia, E. D. & Brivanlou, A. H. Self-organization of a human organizer by combined Wnt and Nodal signalling.Chang, C.-H. & Davies, J. A. 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Production of kidney organoids arranged around single ureteric bud trees, and containing endogenous blood vessels, solely from embryonic stem cells.Wilson, S. B., Santos, I. P., Wildfang, L., Imsa, K. & Little, M. H. Generation of multi-lineage kidney assembloids with integration between nephrons and a single exiting collecting duct. Preprint atKamei, C. N., Gallegos, T. F., Liu, Y., Hukriede, N. & Drummond, I. A. Wnt signaling mediates new nephron formation during zebrafish kidney regeneration.Drake, K. A. et al. Transcription factors YAP/TAZ and SRF cooperate to specify renal myofibroblasts in the developing mouse kidney.Hum, S., Rymer, C., Schaefer, C., Bushnell, D. & Sims-Lucas, S. Ablation of the renal stroma defines its critical role in nephron progenitor and vasculature patterning.Levinson, R. S. et al. FOXD1-dependent signals control cellularity in the renal capsule, a structure required for normal renal development.Google Scholar Munro, D. A. D. & Davies, J. A. Vascularizing the kidney in the embryo and organoid: questioning assumptions about renal vasculogenesis.Luo, P. M., Gu, X., Chaney, C., Carroll, T. & Cleaver, O. Stromal netrin 1 coordinates renal arteriogenesis and mural cell differentiation.Munro, D. A. D., Hohenstein, P. & Davies, J. A. Cycles of vascular plexus formation within the nephrogenic zone of the developing mouse kidney.Maggiore, J. C. et al. A genetically inducible endothelial niche enables vascularization of human kidney organoids with multilineage maturation and emergence of renin expressing cells.van den Berg, C. W. et al. Renal subcapsular transplantation of PSC-derived kidney organoids induces neo-vasculogenesis and significant glomerular and tubular maturation in vivo.van den Berg, C. W., Koudijs, A., Ritsma, L. & Rabelink, T. J. In vivo assessment of size-selective glomerular sieving in transplanted human induced pluripotent stem cell-derived kidney organoids.Tran, T. et al. A scalable organoid model of human autosomal dominant polycystic kidney disease for disease mechanism and drug discovery.Cruz, N. M. et al. Modelling ciliopathy phenotypes in human tissues derived from pluripotent stem cells with genetically ablated cilia.Majumdar, A., Vainio, S., Kispert, A., McMahon, J. & McMahon, A. P. Wnt11 and RET/GDNF pathways cooperate in regulating ureteric branching during metanephric kidney development.We thank L. Prahl for helpful suggestions. This work was supported by NIH National Institute of General Medical Sciences Maximizing Investigators’ Research Award R35GM133380, NIH National Institute of Diabetes and Digestive and Kidney Diseases R01DK132296, NIDDK R01DK140070 and National Science Foundation CAREER award 2047271 .Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USABioengineering Graduate Group, University of Pennsylvania, Philadelphia, PA, USAAlex J. Hughesthanks Matthias Lütolf, Ton Rabelink and the other, anonymous, reviewer for their contribution to the peer review of this work.Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author or other rightsholder; author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
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