Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
Center for Soft and Living Matter, University of Pennsylvania, Philadelphia, PA, USA.
Nat Mater. 2024 Nov;23(11):1582-1591. doi: 10.1038/s41563-024-02019-3. Epub 2024 Oct 9.
Urinary collecting tubules form during kidney embryogenesis through the branching of the ureteric bud epithelium. A travelling mesenchyme niche of nephron progenitor cells caps each branching ureteric bud tip. These 'tip domain' niches pack more closely over developmental time and their number relates to nephron endowment at birth. Yet, how the crowded tissue environment impacts niche number and cell decision-making remains unclear. Here, through experiments and mathematical modelling, we show that niche packing conforms to physical limitations imposed by kidney curvature. We relate packing geometries to rigidity theory to predict a stiffening transition starting at embryonic day 15 in the mouse, validated by micromechanical analysis. Using a method to estimate tip domain 'ages' relative to their most recent branch events, we find that new niches overcome mechanical resistance as they branch and displace neighbours. This creates rhythmic mechanical stress in the niche. These findings expand our understanding of kidney development and inform engineering strategies for synthetic regenerative tissues.
尿收集管在肾脏胚胎发生过程中通过输尿管芽上皮的分支形成。一个移动的肾单位祖细胞间充质龛覆盖每个分支的输尿管芽尖端。随着发育时间的推移，这些“尖端域”龛更加紧密地堆积，它们的数量与出生时的肾单位数量有关。然而，拥挤的组织环境如何影响龛的数量和细胞决策仍不清楚。在这里，我们通过实验和数学建模表明，龛的包装符合由肾脏曲率施加的物理限制。我们将包装几何形状与刚性理论联系起来，以预测从胚胎第 15 天开始的刚性转变，这一预测通过微力学分析得到了验证。使用一种方法来估计相对于最近分支事件的尖端域“年龄”，我们发现新的龛在分支和置换邻居时克服了机械阻力。这会在龛中产生有节奏的机械应力。这些发现扩展了我们对肾脏发育的理解，并为合成再生组织的工程策略提供了信息。
