The Rhesus Macaque Serves As a Model for Human Lateral Branch Nephrogenesis
| Autor: | Andrew S. Potter, Lyan Alkhudairy, S. Steven Potter, Kairavee Thakkar, Meredith P. Schuh, Nathan Salomonis, Raphael Kopan, Kashish Chetal |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Fetus Kidney Kidney development General Medicine Nephron Biology biology.organism_classification Andrology 03 medical and health sciences Rhesus macaque 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Nephrology medicine Progenitor cell 030217 neurology & neurosurgery Immunostaining Progenitor |
| Zdroj: | Journal of the American Society of Nephrology. 32:1097-1112 |
| ISSN: | 1533-3450 1046-6673 |
| Popis: | Background Most nephrons are added in late gestation. Truncated extrauterine nephrogenesis in premature infants results in fewer nephrons and significantly increased risk for CKD in adulthood. To overcome the ethical and technical difficulties associated with studies of late-gestation human fetal kidney development, third-trimester rhesus macaques served as a model to understand lateral branch nephrogenesis (LBN) at the molecular level. Methods Immunostaining and 3D rendering assessed morphology. Single-cell (sc) and single-nucleus (sn) RNA-Seq were performed on four cortically enriched fetal rhesus kidneys of 129-131 days gestational age (GA). An integrative bioinformatics strategy was applied across single-cell modalities, species, and time. RNAScope validation studies were performed on human archival tissue. Results Third-trimester rhesus kidney undergoes human-like LBN. scRNA-Seq of 23,608 cells revealed 37 transcriptionally distinct cell populations, including naive nephron progenitor cells (NPCs), with the prior noted marker genes CITED1, MEOX1, and EYA1 (c25). These same populations and markers were reflected in snRNA-Seq of 5972 nuclei. Late-gestation rhesus NPC markers resembled late-gestation murine NPC, whereas early second-trimester human NPC markers aligned to midgestation murine NPCs. New, age-specific rhesus NPCs (SHISA8) and ureteric buds (POU3F4 and TWIST) predicted markers were verified in late-gestation human archival samples. Conclusions Rhesus macaque is the first model of bona fide LBN, enabling molecular studies of late gestation, human-like nephrogenesis. These molecular findings support the hypothesis that aging nephron progenitors have a distinct molecular signature and align to their earlier human counterparts, with unique markers highlighting LBN-specific progenitor maturation. |
| Databáze: | OpenAIRE |
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