Olczak Alicja, Pieczonka Tomasz D, Ławicki Szymon, Łukaszyk Konrad, Pulawska-Czub Anna, Cambier Linda, Kobielak Krzysztof
Centre of New Technologies (CeNT), University of Warsaw (UW), Warsaw, Poland.
The Vision Center and The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, United States.
Front Physiol. 2024 Sep 16;15:1424077. doi: 10.3389/fphys.2024.1424077. eCollection 2024.
Mice hair follicles (HFs) are a valuable model for studying various aspects of hair biology, including morphogenesis, development, and regeneration due to their easily observable phenotype and genetic manipulability. The initiation and progression of hair follicle morphogenesis, as well as the hair follicle cycle, are regulated by various signaling pathways, of which the main role is played by the Wingless-type MMTV integration site family (Wnt) and the Bone Morphogenic Protein (BMP). During the hair follicle cycle, the BMP pathway maintains hair follicle stem cells (HFSCs) in a dormant state while the Wnt pathway activates them for hair growth. Given the pivotal role of the Wnt pathway in hair biology and HFSCs regulation, we investigated the influence of the Wnt modulator - R-spondin 3 (Rspo3), in these processes. For this purpose, we developed a transgenic mice model with the overexpression of (Rspo3GOF) in the whole ectoderm and its derivatives, starting from early morphogenesis. Rspo3GOF mice exhibited a distinct phenotype with sparse hair and visible bald areas, caused by reduced proliferation and increased apoptosis of hair matrix progenitor cells, which resulted in a premature anagen-to-catagen transition with a shortened growth phase and decreased overall length of all hair types. In addition, Rspo3GOF promoted induction of auchene and awl, canonical Wnt-dependent hair type during morphogenesis, but the overall hair amount remained reduced. We also discovered a delay in the pre-bulge formation during morphogenesis and prolonged immaturity of the HFSC population in the bulge region postnatally, which further impaired proper hair regeneration throughout the mice's lifespan. Our data supported that function observed in our model works in HFSCs' formation of pre-bulge during morphogenesis via enhancing activation of the canonical Wnt pathway, whereas in contrast, in the postnatal immature bulge, activation of canonical Wnt signaling was attenuated. studies on keratinocytes revealed changes in proliferation, migration, and colony formation, highlighting the inhibitory effect of constitutive overexpression of on these cellular processes. Our research provides novel insights into the role of in the regulation of hair morphogenesis and development, along with the formation and maturation of the HFSCs, which affect hair regeneration.
小鼠毛囊是研究毛发生物学各个方面的宝贵模型，包括形态发生、发育和再生，这是由于其易于观察的表型和遗传可操作性。毛囊形态发生的起始和进展以及毛囊周期受多种信号通路调控，其中无翅型MMTV整合位点家族（Wnt）和骨形态发生蛋白（BMP）起主要作用。在毛囊周期中，BMP通路使毛囊干细胞（HFSC）处于休眠状态，而Wnt通路激活它们以促进毛发生长。鉴于Wnt通路在毛发生物学和HFSC调控中的关键作用，我们研究了Wnt调节剂R-spondin 3（Rspo3）在这些过程中的影响。为此，我们构建了一种转基因小鼠模型，从早期形态发生开始，在整个外胚层及其衍生物中过表达Rspo3（Rspo3GOF）。Rspo3GOF小鼠表现出明显的表型，毛发稀疏且有明显秃斑，这是由毛基质祖细胞增殖减少和凋亡增加所致，导致生长期过早向退行期转变，生长期缩短，所有毛发类型的总长度减少。此外，Rspo3GOF促进了形态发生过程中典型Wnt依赖的毛发类型——须毛和锥毛的诱导，但毛发总量仍减少。我们还发现形态发生过程中隆突前形成延迟，出生后隆突区域HFSC群体的不成熟期延长，这进一步损害了小鼠整个生命周期中的正常毛发再生。我们的数据支持，我们模型中观察到的Rspo3功能通过增强典型Wnt通路的激活在形态发生过程中HFSC的隆突前形成中起作用，而相反，在出生后不成熟的隆突中，典型Wnt信号的激活减弱。对角质形成细胞的研究揭示了增殖、迁移和集落形成的变化，突出了Rspo3组成型过表达对这些细胞过程的抑制作用。我们的研究为Rspo3在毛发形态发生和发育调控以及影响毛发再生的HFSC形成和成熟中的作用提供了新的见解。
