Krt5+ urothelial cells are developmental and tissue repair progenitors in the kidney
Krt5+ urothelial cells are developmental and tissue repair progenitors in the kidney
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DOI：
10.1152/ajprenal.00171.2019
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发表时间：
2019-09-01
影响因子：
4.2
通讯作者：
Becknell, Brian
中科院分区：
文献类型：
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作者：
Jackson, Ashley R.;Hoff, Monica L.;Becknell, Brian
先天性尿路梗阻(UTO)是儿童慢性肾脏疾病的主要原因；然而，目前的治疗策略并不能预防进展为终末期肾病，这突出了干预措施的必要性，以限制或逆转梗阻性肾病。实验性UTO可触发肾脏尿路上皮重塑，最终导致基底角蛋白5阳性(Krt5(+))肾尿路上皮细胞(RUCs)重新分布，并产生UPK(+)RUCs，合成保护性顶端尿路上皮斑块。UPK(-)RUCs的细胞来源目前尚不清楚，这限制了促进肾脏尿路上皮重塑作为一种治疗方法的策略的发展。在本研究中，我们追踪了成人UPK(+)RUC在正常发育和对UTO的反应中的起源。命运图谱分析表明，成年UPK(-)RUCs来源于胚胎和新生Krt5(+)RUCs，而Krt5(+)RUCs失去这种祖细胞能力，并在出生后14天成为谱系限制。然而，出生后14天标记的成年Krt5(+)RUC打破了它们的谱系限制，强烈分化为UPK+RUC。因此，Krt5(+)RUC在正常个体发育期间和UTO后通过以时间受限的方式分化为UPK(+)RUC来驱动肾上皮细胞的形成。
Congenital urinary tract obstruction (UTO) is the leading cause of chronic kidney disease in children; however, current management strategies do not safeguard against progression to end-stage renal disease, highlighting the need for interventions to limit or reverse obstructive nephropathy. Experimental UTO triggers renal urothelial remodeling that culminates in the redistribution of basal keratin 5-positive (Krt5(+)) renal urothelial cells (RUCs) and the generation of uroplakin-positive (Upk)(+) RUCs that synthesize a protective apical urothelial plaque. The cellular source of Upk(-) RUCs is currently unknown, limiting the development of strategies to promote renal urothelial remodeling as a therapeutic approach. In the present study, we traced the origins of adult Upk(+) RUCs during normal development and in response to UTO. Fate mapping analysis demonstrated that adult Upk(-) RUCs derive from embryonic and neonatal Krt5(+) RUCs, whereas Krt5(+) RUCs lose this progenitor capacity and become lineage restricted by postnatal day 14. However, in response to UTO, postnatal day 14-labeled adult Krt5(+) RUCs break their lineage restriction and robustly differentiate into Upk+ RUCs. Thus, Krt5(+) RUCs drive renal urothelial formation during normal ontogeny and after UTO by differentiating into Upk(+) RUCs in a temporally restricted manner.