Self‐organizing hair peg‐like structures from dissociated skin progenitor cells: new insights for human hair follicle organoid engineering and Turing patterning in an asymmetric morphogenetic field

Human skin progenitor cells will form new hair follicles, although at a low efficiency, when injected into nude mouse skin. To better study and improve upon this regenerative process, we developed an in vitro system to analyze the morphogenetic cell behavior in detail and modulate physical‐chemical parameters to more effectively generate hair primordia. In this three‐dimensional culture, dissociated human neonatal foreskin keratinocytes self‐assembled into a planar epidermal layer while fetal scalp dermal cells coalesced into stripes, then large clusters, and finally small clusters resembling dermal condensations. At sites of dermal clustering, subjacent epidermal cells protruded to form hair peg‐like structures, molecularly resembling hair pegs within the sequence of follicular development. The hair peg‐like structures emerged in a coordinated, formative wave, moving from periphery to center, suggesting that the droplet culture constitutes a microcosm with an asymmetric morphogenetic field. In vivo, hair follicle populations also form in a progressive wave, implying the summation of local periodic patterning events with an asymmetric global influence. To further understand this global patterning process, we developed a mathematical simulation using Turing activator‐inhibitor principles in an asymmetric morphogenetic field. Together, our culture system provides a suitable platform to 1) analyze the self‐assembly behavior of hair progenitor cells into periodically arranged hair primordia, and 2) identify parameters that impact the formation of hair primordia in an asymmetric morphogenetic field. This understanding will enhance our future ability to successfully engineer human hair follicle organoids.