The control principles behind robust cyclic regeneration of hair follicles (HFs) remain unclear. Using multi-scale modeling, we show that coupling inhibitors and activators with physical growth of HFs is sufficient to drive periodicity and excitability of hair regeneration. Model simulations and experimental data reveal that mouse skin behaves as a heterogeneous regenerative field, composed of anatomical domains where HFs have distinct cycling dynamics. Interactions between fast-cycling chin and ventral HFs and slow-cycling dorsal HFs produce bilaterally symmetric patterns. Ear skin behaves as a hyper-refractory domain with HFs in extended rest phase. Such hyper-refractivity relates to high levels of BMP ligands and WNT antagonists, in part expressed by ear-specific cartilage and muscle. Hair growth stops at the boundaries with hyper-refractory ears and anatomically discontinuous eyelids, generating wave-breaking effects. We posit that similar mechanisms for coupled regeneration with dominant activator, hyper-refractory, and wave-breaker regions can operate in other actively renewing organs.

Maintenance of trichogenecity of dermal papilla cells (DPCs) have been a problem during cell therapy for androgenic alopecia, as they lose their regenerative potential in in vitro culture. Various spheroid culture techniques are used to increase and maintain trichogenecity of these cells. However, there are some critical drawbacks in these methods. Applying a hydrocell plate for sphere formation or hanging drop methods by hand would be difficult to control the size and cell density inside it. It would be difficult to commercialize or mass production for clinical therapy. In aim to address and overcome these drawbacks, we have introduced alginate sphere. The alginate sphere of DPCs were prepared by electrospinning at different voltages to control the size of sphere. Then the obtained alginate spheres were evaluated for cellular dynamics and density of DPCs under different conditions. In this study, we found that DPCs do not proliferate in alginate sphere. However, the number of DPCs were maintained and found to be in dormant state. Further, the dormant DPCs in the alginate sphere have upregulated DPC signature genes (SOX2, ALPL, WIF1, Noggin, BMP4 and VCAN) and proliferative capacity. Thus, we speculate that alginate sphere environment maintains the dormancy of DPCs with increased trichogenecity.