In the prevailing model, Lgr5+ cells are the only intestinal stem cells (ISCs) that sustain homeostatic epithelial regeneration by upward migration of progeny through elusive upper crypt transit-amplifying (TA) intermediates. Here, we identify a proliferative upper crypt population marked by Fgfbp1, in the location of putative TA cells, that is transcriptionally distinct from Lgr5+ cells. Using a kinetic reporter for time-resolved fate mapping and Fgfbp1-CreER^T2 lineage tracing, we establish that Fgfbp1+ cells are multi-potent and give rise to Lgr5+ cells, consistent with their ISC function. Fgfbp1+ cells also sustain epithelial regeneration following Lgr5+ cell depletion. We demonstrate that FGFBP1, produced by the upper crypt cells, is an essential factor for crypt proliferation and epithelial homeostasis. Our findings support a model in which tissue regeneration originates from upper crypt Fgfbp1+ cells that generate progeny propagating bi-directionally along the crypt-villus axis and serve as a source of Lgr5+ cells in the crypt base.

在流行的模型中， Lgr5 +细胞是唯一能够通过难以捉摸的上隐窝转运放大（TA）中间体向上迁移后代来维持稳态上皮再生的肠干细胞（ISC）。在这里，我们在假定的 TA 细胞位置鉴定了由Fgfbp1标记的增殖性上隐窝群体，其转录与Lgr5 + 细胞不同。使用动力学报告器进行时间分辨命运图谱和Fgfbp1-CreER ^T2谱系追踪，我们确定Fgfbp1 + 细胞是多能的，并产生Lgr5 + 细胞，与其 ISC 功能一致。 Lgr5 + 细胞耗竭后， Fgfbp1 + 细胞也能维持上皮再生。我们证明，由上隐窝细胞产生的 FGFBP1 是隐窝增殖和上皮稳态的重要因素。我们的研究结果支持这样一种模型，其中组织再生源自上隐窝Fgfbp1 + 细胞，这些细胞产生沿隐窝绒毛轴双向繁殖的后代，并作为隐窝基部Lgr5 + 细胞的来源。