Patterning human kidney organoids with synthetic Wnt-secreting organizers.
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| Title: | Patterning human kidney organoids with synthetic Wnt-secreting organizers. |
|---|---|
| Authors: | Fausto, Connor C. (AUTHOR), Glykofrydis, Fokion (AUTHOR), Kumar, Navneet (AUTHOR), Schnell, Jack (AUTHOR), Csipan, Reka L. (AUTHOR), De Kuyper, Faith (AUTHOR), Kunnan, Minnal (AUTHOR), Grubbs, Brendan (AUTHOR), Thornton, Matthew (AUTHOR), Thompson, Michael (AUTHOR), Chang, Enmian (AUTHOR), Wen, Xuduo (AUTHOR), Pelayo, Manuel (AUTHOR), Achieng, MaryAnne (AUTHOR), Seth, Anoothi (AUTHOR), Street, Kelly (AUTHOR), Morsut, Leonardo (AUTHOR), Lindström, Nils O. (AUTHOR) |
| Source: | Science. 7/2/2026, Vol. 393 Issue 6806, p1-11. 11p. |
| Subjects: | Wnt signal transduction, Spatial arrangement, Stem cells, Kidney tubules, Organoids, Transcriptomes |
| Abstract: | Human stem cell–derived miniature organs, including kidney organoids, reproduce aspects of tissue development but lack reliable spatial patterning. In embryos, spatial organization is often established by developmental organizers that generate morphogenetic fields. However, how such organizing geometry operates in kidney nephrogenesis—and whether it can be reconstructed in vitro—has remained unclear. Using spatial transcriptomics of human kidney development, we found that nascent nephrons establish a collecting duct adjacent-to-distant polarity bordering a WNT11-WNT9B signaling boundary. Engineered WNT-secreting cellular organizers introduced into kidney organoids restored this organizing geometry, biasing distal nephron differentiation and orienting nephron morphogenesis toward the signal source, which demonstrates that developmental signaling geometry can be reconstructed synthetically to control tissue patterning. Editor's summary: The creation of functional kidney tissue in vitro would provide an ideal solution to treating kidney failure, but the recreation of complex nephron structures that allow fluid filtration and flow into connecting ducts is a daunting challenge. Fausto et al. describe a step in that direction by recreating a key signaling mechanism in nephron formation in tissue culture. Single-cell RNA sequencing and spatial transcriptomics of developing human kidney nephrons showed that they form a signaling boundary where connecting duct cells produce WNT morphogens. Introducing synthetic WNT-secreting organizers made from modified human embryonic kidney cells helped to restore proper spatial organization in developing organoids. This study provides a step toward more effective understanding of tissue patterning and synthetic recreation of organs. —L. Bryan Ray INTRODUCTION: Organoids—miniature tissues grown from stem cells—can reproduce aspects of organ development, but their architecture often emerges through self-organization and is therefore difficult to control. Understanding how to impose spatial patterning in organoid systems is therefore an important challenge. Kidney organoids illustrate this limitation. Unlike in vivo nephrons, which form long segmented tubules oriented so that filtered fluid drains into a common collecting system, organoid nephrons exhibit variable patterning and orientation. This lack of spatial organization limits the ability of kidney organoids to form coherent nephron architectures and to model normal nephron physiologies. RATIONALE: In embryos, spatial patterning is often organized by localized signaling centers known as developmental organizers. In the kidney, nephrons form next to the developing and branching collecting duct, and work in model organisms suggests that this epithelium provides localized signals that guide nephron polarity and segmentation. How this organizing geometry is arranged in human development and which cues are sufficient to recreate it have remained unclear. We mapped this organizing geometry in developing human kidneys and tested whether a minimal cue of localized WNT signaling could restore spatial control of nephron patterning in organoids. RESULTS: Spatial transcriptomics revealed that nascent human nephrons form adjacent to a boundary in the collecting duct where two WNT signaling proteins, WNT11 and WNT9B, mark neighboring tip and stalk domains. Forming nephrons displayed asymmetric gene expression relative to the WNT9B-expressing collecting duct. This finding allowed us to define an adjacent-to-distant axial nephron polarity that emerges early and persists as nephrons elongate and simultaneously form their proximal-distal axes. WNT response genes were enriched near the WNT9B domain, consistent with localized WNT signaling at the nephron–to–collecting duct interface. We tested whether this signaling geometry is sufficient to guide organoid architecture and engineered self-assembling WNT-secreting "synthetic organizers." When placed next to kidney organoids, nephrons adjacent to organizers showed restored localized WNT responses, acquired axial polarity, and oriented tubule growth and segment patterning toward the signal source. Tuning of organizer output controlled nephron architecture and revealed conditions in which nephrons generate multiple segments while remaining coherently oriented. CONCLUSION: Our findings link a spatial organizing geometry in the developing human kidney to controllable engineering in vitro. Synthetic organizers provide a modular way to restore missing spatial interactions without reconstructing the entire collecting duct lineage, complementing approaches that rebuild collecting duct–to–nephron cellular interactions. More broadly, combining in vivo spatial mapping with synthetic reconstruction provides a general pipeline to identify organizer geometries in developing tissues and recreate them to guide organ morphogenesis. WNT organizers control nephron patterning.: Spatial transcriptomics of the developing human kidney reveals a WNT11-WNT9B boundary at the collecting duct that establishes an adjacent-distant polarity guiding nephron morphogenesis. Kidney organoids lack this spatial organizer and show disorganized patterning. Introducing tunable synthetic WNT-secreting organizers restores localized signaling, inducing symmetry breaking, orienting nephron growth and enabling controlled nephron patterning in organoids. CD, collecting duct. [ABSTRACT FROM AUTHOR] |
| Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Psychology and Behavioral Sciences Collection |
| FullText | Text: Availability: 0 |
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| Header | DbId: pbh DbLabel: Psychology and Behavioral Sciences Collection An: 195069937 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Patterning human kidney organoids with synthetic Wnt-secreting organizers. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Fausto%2C+Connor+C%2E%22">Fausto, Connor C.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Glykofrydis%2C+Fokion%22">Glykofrydis, Fokion</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kumar%2C+Navneet%22">Kumar, Navneet</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Schnell%2C+Jack%22">Schnell, Jack</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Csipan%2C+Reka+L%2E%22">Csipan, Reka L.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22De+Kuyper%2C+Faith%22">De Kuyper, Faith</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kunnan%2C+Minnal%22">Kunnan, Minnal</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Grubbs%2C+Brendan%22">Grubbs, Brendan</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Thornton%2C+Matthew%22">Thornton, Matthew</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Thompson%2C+Michael%22">Thompson, Michael</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Chang%2C+Enmian%22">Chang, Enmian</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Wen%2C+Xuduo%22">Wen, Xuduo</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Pelayo%2C+Manuel%22">Pelayo, Manuel</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Achieng%2C+MaryAnne%22">Achieng, MaryAnne</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Seth%2C+Anoothi%22">Seth, Anoothi</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Street%2C+Kelly%22">Street, Kelly</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Morsut%2C+Leonardo%22">Morsut, Leonardo</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Lindström%2C+Nils+O%2E%22">Lindström, Nils O.</searchLink> (AUTHOR) – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Science%22">Science</searchLink>. 7/2/2026, Vol. 393 Issue 6806, p1-11. 11p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Wnt+signal+transduction%22">Wnt signal transduction</searchLink><br /><searchLink fieldCode="DE" term="%22Spatial+arrangement%22">Spatial arrangement</searchLink><br /><searchLink fieldCode="DE" term="%22Stem+cells%22">Stem cells</searchLink><br /><searchLink fieldCode="DE" term="%22Kidney+tubules%22">Kidney tubules</searchLink><br /><searchLink fieldCode="DE" term="%22Organoids%22">Organoids</searchLink><br /><searchLink fieldCode="DE" term="%22Transcriptomes%22">Transcriptomes</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Human stem cell–derived miniature organs, including kidney organoids, reproduce aspects of tissue development but lack reliable spatial patterning. In embryos, spatial organization is often established by developmental organizers that generate morphogenetic fields. However, how such organizing geometry operates in kidney nephrogenesis—and whether it can be reconstructed in vitro—has remained unclear. Using spatial transcriptomics of human kidney development, we found that nascent nephrons establish a collecting duct adjacent-to-distant polarity bordering a WNT11-WNT9B signaling boundary. Engineered WNT-secreting cellular organizers introduced into kidney organoids restored this organizing geometry, biasing distal nephron differentiation and orienting nephron morphogenesis toward the signal source, which demonstrates that developmental signaling geometry can be reconstructed synthetically to control tissue patterning. Editor's summary: The creation of functional kidney tissue in vitro would provide an ideal solution to treating kidney failure, but the recreation of complex nephron structures that allow fluid filtration and flow into connecting ducts is a daunting challenge. Fausto et al. describe a step in that direction by recreating a key signaling mechanism in nephron formation in tissue culture. Single-cell RNA sequencing and spatial transcriptomics of developing human kidney nephrons showed that they form a signaling boundary where connecting duct cells produce WNT morphogens. Introducing synthetic WNT-secreting organizers made from modified human embryonic kidney cells helped to restore proper spatial organization in developing organoids. This study provides a step toward more effective understanding of tissue patterning and synthetic recreation of organs. —L. Bryan Ray INTRODUCTION: Organoids—miniature tissues grown from stem cells—can reproduce aspects of organ development, but their architecture often emerges through self-organization and is therefore difficult to control. Understanding how to impose spatial patterning in organoid systems is therefore an important challenge. Kidney organoids illustrate this limitation. Unlike in vivo nephrons, which form long segmented tubules oriented so that filtered fluid drains into a common collecting system, organoid nephrons exhibit variable patterning and orientation. This lack of spatial organization limits the ability of kidney organoids to form coherent nephron architectures and to model normal nephron physiologies. RATIONALE: In embryos, spatial patterning is often organized by localized signaling centers known as developmental organizers. In the kidney, nephrons form next to the developing and branching collecting duct, and work in model organisms suggests that this epithelium provides localized signals that guide nephron polarity and segmentation. How this organizing geometry is arranged in human development and which cues are sufficient to recreate it have remained unclear. We mapped this organizing geometry in developing human kidneys and tested whether a minimal cue of localized WNT signaling could restore spatial control of nephron patterning in organoids. RESULTS: Spatial transcriptomics revealed that nascent human nephrons form adjacent to a boundary in the collecting duct where two WNT signaling proteins, WNT11 and WNT9B, mark neighboring tip and stalk domains. Forming nephrons displayed asymmetric gene expression relative to the WNT9B-expressing collecting duct. This finding allowed us to define an adjacent-to-distant axial nephron polarity that emerges early and persists as nephrons elongate and simultaneously form their proximal-distal axes. WNT response genes were enriched near the WNT9B domain, consistent with localized WNT signaling at the nephron–to–collecting duct interface. We tested whether this signaling geometry is sufficient to guide organoid architecture and engineered self-assembling WNT-secreting "synthetic organizers." When placed next to kidney organoids, nephrons adjacent to organizers showed restored localized WNT responses, acquired axial polarity, and oriented tubule growth and segment patterning toward the signal source. Tuning of organizer output controlled nephron architecture and revealed conditions in which nephrons generate multiple segments while remaining coherently oriented. CONCLUSION: Our findings link a spatial organizing geometry in the developing human kidney to controllable engineering in vitro. Synthetic organizers provide a modular way to restore missing spatial interactions without reconstructing the entire collecting duct lineage, complementing approaches that rebuild collecting duct–to–nephron cellular interactions. More broadly, combining in vivo spatial mapping with synthetic reconstruction provides a general pipeline to identify organizer geometries in developing tissues and recreate them to guide organ morphogenesis. WNT organizers control nephron patterning.: Spatial transcriptomics of the developing human kidney reveals a WNT11-WNT9B boundary at the collecting duct that establishes an adjacent-distant polarity guiding nephron morphogenesis. Kidney organoids lack this spatial organizer and show disorganized patterning. Introducing tunable synthetic WNT-secreting organizers restores localized signaling, inducing symmetry breaking, orienting nephron growth and enabling controlled nephron patterning in organoids. CD, collecting duct. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1126/science.adu9122 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 11 StartPage: 1 Subjects: – SubjectFull: Wnt signal transduction Type: general – SubjectFull: Spatial arrangement Type: general – SubjectFull: Stem cells Type: general – SubjectFull: Kidney tubules Type: general – SubjectFull: Organoids Type: general – SubjectFull: Transcriptomes Type: general Titles: – TitleFull: Patterning human kidney organoids with synthetic Wnt-secreting organizers. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Fausto, Connor C. – PersonEntity: Name: NameFull: Glykofrydis, Fokion – PersonEntity: Name: NameFull: Kumar, Navneet – PersonEntity: Name: NameFull: Schnell, Jack – PersonEntity: Name: NameFull: Csipan, Reka L. – PersonEntity: Name: NameFull: De Kuyper, Faith – PersonEntity: Name: NameFull: Kunnan, Minnal – PersonEntity: Name: NameFull: Grubbs, Brendan – PersonEntity: Name: NameFull: Thornton, Matthew – PersonEntity: Name: NameFull: Thompson, Michael – PersonEntity: Name: NameFull: Chang, Enmian – PersonEntity: Name: NameFull: Wen, Xuduo – PersonEntity: Name: NameFull: Pelayo, Manuel – PersonEntity: Name: NameFull: Achieng, MaryAnne – PersonEntity: Name: NameFull: Seth, Anoothi – PersonEntity: Name: NameFull: Street, Kelly – PersonEntity: Name: NameFull: Morsut, Leonardo – PersonEntity: Name: NameFull: Lindström, Nils O. IsPartOfRelationships: – BibEntity: Dates: – D: 02 M: 07 Text: 7/2/2026 Type: published Y: 2026 Identifiers: – Type: issn-print Value: 00368075 Numbering: – Type: volume Value: 393 – Type: issue Value: 6806 Titles: – TitleFull: Science Type: main |
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