Organoids made from dissociated progenitor cells undergo tissue-like organization. This in vitro self-organization process is not identical to embryonic organ formation, but it achieves a similar phenotype in vivo. This implies genetic codes do not specify morphology directly; instead, complex tissue architectures may be achieved through several intermediate layers of cross talk between genetic information and biophysical processes. Here we use newborn and adult skin organoids for analyses. Dissociated cells from newborn mouse skin form hair primordia-bearing organoids that grow hairs robustly in vivo after transplantation to nude mice. Detailed time-lapse imaging of 3D cultures revealed unexpected morphological transitions between six distinct phases: dissociated cells, cell aggregates, polarized cysts, cyst coalescence, planar skin, and hair-bearing skin. Transcriptome profiling reveals the sequential expression of adhesion molecules, growth factors, Wnts, and matrix metalloproteinases (MMPs). Functional perturbations at different times discern their roles in regulating the switch from one phase to another. In contrast, adult cells form small aggregates, but then development stalls in vitro. Comparative transcriptome analyses suggest suppressing epidermal differentiation in adult cells is critical. These results inspire a strategy that can restore morphological transitions and rescue the hair-forming ability of adult organoids: (i) continuous PKC inhibition and (ii) timely supply of growth factors (IGF, VEGF), Wnts, and MMPs. This comprehensive study demonstrates that alternating molecular events and physical processes are in action during organoid morphogenesis and that the self-organizing processes can be restored via environmental reprogramming. This tissue-level phase transition could drive self-organization behavior in organoid morphogenies beyond the skin.

Introduction: There are major new advancements in the fields of stem cell biology, developmental biology, regenerative hair cycling, and tissue engineering. The time is ripe to integrate, translate...

Keloids are fibroproliferative skin disorder caused by abnormal healing of injured or irritated skin and are characterized by excessive extracellular matrix (ECM) synthesis and deposition, which results in excessive collagen disorders and calcinosis, increasing the remodeling and stiffness of keloid matrix. The pathogenesis of keloid is very complex, and may include changes in cell function, genetics, inflammation, and other factors. In this review, we aim to discuss the role of biomechanical factors in keloid formation. Mechanical stimulation can lead to excessive proliferation of wound fibroblasts, deposition of ECM, secretion of more pro-fibrosis factors, and continuous increase of keloid matrix stiffness. Matrix mechanics resulting from increased matrix stiffness further activates the fibrotic phenotype of keloid fibroblasts, thus forming a loop that continuously invades the surrounding normal tissue. In this process, mechanical force is one of the initial factors of keloid formation, and matrix mechanics leads to further keloid development. Next, we summarized the mechanotransduction pathways involved in the formation of keloids, such as TGF-β/Smad signaling pathway, integrin signaling pathway, YAP/TAZ signaling pathway, and calcium ion pathway. Finally, some potential biomechanics-based therapeutic concepts and strategies are described in detail. Taken together, these findings underscore the importance of biomechanical factors in the formation and progression of keloids and highlight their regulatory value. These findings may help facilitate the development of pharmacological interventions that can ultimately prevent and reduce keloid formation and progression.

Skin evolves essential appendages and indispensable types of cells that synergistically insulate the body from environmental insults. Residing in the specific regions in the skin such as epidermis, dermis and hair follicle, melanocytes perform an array of vital functions including defending the ultraviolet radiation and diversifying animal appearance. As one of the adult stem cells, melanocyte stem cells in the hair follicle bulge niche can proliferate, differentiate and keep quiescence to control and coordinate tissue homeostasis, repair and regeneration. In synchrony with hair follicle stem cells, melanocyte stem cells in the hair follicles undergo cyclic activation, degeneration and resting phases, to pigment the hairs and to preserve the stem cells. Disorder of melanocytes results in severe skin problems such as canities, vitiligo and even melanoma. Here, we compare and summarize recent discoveries about melanocyte in the skin, particularly in the hair follicle. A better understanding of the physiological and pathological regulation of melanocyte and melanocyte stem cell behaviours will help to guide the clinical applications in regenerative medicine.