The writing of this review was made possible through the Monasterium Laboratory, Germany, and startup funds to R.P. from the University of Miami. T.L. acknowledges funding by the DFG CRC 1182 (TPC4.2). T.C.G.B. gratefully appreciates support of the Canadian Institute for Advanced Research (CIFAR) and the DFG CRC 1182.

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Objective Human hair follicles (HFs) are populated by a rich and diverse microbiome, traditionally evaluated by methods that inadvertently sample the skin microbiome and/or miss microbiota located in deeper HF regions. Thereby, these methods capture the human HF microbiome in a skewed and incomplete manner. This pilot study aimed to use laser-capture microdissection of human scalp HFs, coupled with 16S rRNA gene sequencing to sample the HF microbiome and overcome these methodological limitations. Results HFs were laser-capture microdissected (LCM) into three anatomically distinct regions. All main known core HF bacterial colonisers, including Cutibacterium, Corynebacterium and Staphylococcus, were identified, in all three HF regions. Interestingly, region-specific variations in α-diversity and microbial abundance of the core microbiome genera and Reyranella were identified, suggestive of variations in microbiologically relevant microenvironment characteristics. This pilot study therefore shows that LCM-coupled with metagenomics is a powerful tool for analysing the microbiome of defined biological niches. Refining and complementing this method with broader metagenomic techniques will facilitate the mapping of dysbiotic events associated with HF diseases and targeted therapeutic interventions.

The microbiome of human hair follicles (HFs) has emerged as an important player in different HF and skin pathologies, yet awaits in-depth exploration. This raises questions regarding the tightly linked interactions between host environment, nutrient dependency of host-associated microbes, microbial metabolism, microbe-microbe interactions and host immunity. The use of simple model systems facilitates addressing generally important questions and testing overarching, therapeutically relevant principles that likely transcend obvious interspecies differences. Here, we evaluate the potential of the freshwater polyp Hydra, to dissect fundamental principles of microbiome regulation by the host, that is the human HF. In particular, we focus on therapeutically targetable host-microbiome interactions, such as nutrient dependency, microbial interactions and host defence. Offering a new lens into the study of HFmicrobiota interactions, we argue that general principles of how Hydra manages its microbiota can inform the development of novel, microbiome-targeting therapeutic interventions in human skin disease.

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Androgenetic alopecia is a common form of pattern hair loss, characterized by miniaturized hair follicles (HFs) at the front and parietal scalp, while hairs on the occipital scalp are preserved. Moreover, different body sites exhibit distinct types and patterns of HFs and understanding the molecular basis for this heterogeneity is important to design targeted treatment strategies. The Wnt signalling pathway and its Dickkopf (Dkk) inhibitors have been suggested to regulate HF type and patterning. We have previously shown that Dkk4 is specifically expressed in the epithelial placodes of HFs during mouse skin development. To elucidate the functions of Dkk4 in HF patterning, in this work, we used CRISPR/Cas9 to generate Dkk4-knockout mice. Dkk4 mutants showed disrupted HF patterning where the interplacodal distance was increased. Surprisingly, the lateral back skin of Dkk4 mutants was completely devoid of the first wave of HFs. In order to address the heterogeneity and regional differences in HF formation, we generated a Dkk4-EGFP knockin mouse line, which recapitulated the expression of Dkk4 in HF placodes. Our data revealed intra-and interplacodal differences in the expression of Dkk4-EGFP, suggesting that a WNT-DKK axis underlies the regional specificities in HF induction and patterning. Elucidating the molecular mechanisms of this heterogeneity will shed light on hair loss patterns such as in androgenetic alopecia.