Department of Internal Medicine I University Hospital Ulm Albert-Einstein Allee 23 89081 Ulm Germany.
Institute for Diabetes and Regeneration Helmholtz Zentrum München Ingolstädter Landstraße 1 85764 Neuherberg Germany.
Adv Sci (Weinh). 2021 May 13;8(14):2100626. doi: 10.1002/advs.202100626. eCollection 2021 Jul.
Somatic cell reprogramming and tissue repair share relevant factors and molecular programs. Here, Dickkopf-3 (DKK3) is identified as novel factor for organ regeneration using combined transcription-factor-induced reprogramming and RNA-interference techniques. Loss of enhances the generation of induced pluripotent stem cells but does not affect de novo derivation of embryonic stem cells, three-germ-layer differentiation or colony formation capacity of liver and pancreatic organoids. However, DKK3 expression levels in wildtype animals and serum levels in human patients are elevated upon injury. Accordingly, -null mice display less liver damage upon acute and chronic failure mediated by increased proliferation in hepatocytes and LGR5 liver progenitor cell population, respectively. Similarly, recovery from experimental pancreatitis is accelerated. Regeneration onset occurs in the acinar compartment accompanied by virtually abolished canonical-Wnt-signaling in -null animals. This results in reduced expression of the Hedgehog repressor and increased Hedgehog-signaling activity upon loss. Collectively, these data reveal as a key regulator of organ regeneration via a direct, previously unacknowledged link between DKK3, canonical-Wnt-, and Hedgehog-signaling.
体细胞重编程和组织修复共享相关的因素和分子程序。在这里，Dickkopf-3（DKK3）被鉴定为使用组合转录因子诱导重编程和 RNA 干扰技术进行器官再生的新型因子。DKK3 的缺失增强了诱导多能干细胞的生成，但不影响胚胎干细胞的从头衍生、三胚层分化或肝和胰腺类器官的集落形成能力。然而，在损伤后，野生型动物中的 DKK3 表达水平和人类患者的血清水平升高。相应地，-/- 小鼠在急性和慢性衰竭介导的肝损伤中表现出较低的损伤，分别是通过肝细胞和 LGR5 肝祖细胞群体的增殖增加。同样，实验性胰腺炎的恢复得到加速。再生起始发生在腺泡区室中，同时在 -/- 动物中几乎消除了经典 Wnt 信号。这导致 Hedgehog 抑制剂 的表达减少，以及 Hedgehog 信号活性增加。总的来说，这些数据揭示了 DKK3、经典 Wnt-和 Hedgehog 信号之间的直接、以前未被认识的联系，作为器官再生的关键调节剂。
