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The nail appendage is composed of several layers that organize the nail organ:

  • The eponychium creates a border between skin epidermis and nail organ at the dorsal limit of the nail proximal fold (NPF), forming a protective seal.

  • The NPF forms after skin epidermis bends inward ventrally at the eponychium’s border and becomes the nail epidermis, creating the NPF, which localizes slow-cycling bifunctional nail proximal fold stem cells (NPFSCs). NPFSCs actively deliver progeny to the perinail epidermis and nail matrix along with differentiated nail plate upon nail regeneration.

  • The matrix, a ventral continuation of the proximal fold after it bends dorsally and distally, is composed of actively proliferating cells called onychocytes. In the proximal nail matrix, fast-proliferating nail stem cells are located. Their differentiation is coupled directly with the ability to orchestrate digit regeneration.

  • Nail matrix differentiates, forming the keratogenous zone, which finally deposit cells into the overlying nail plate.

  • Hyponychium is the most distal part of the nail epithelium located peripherally to the nail bed, and beneath the nail plate at the junction between the free edge and the skin epidermis of the fingertip, it forms a seal that protects the nail bed.


The nail organ is one of the skin appendages located on the distal phalanx of each finger and toe in human body. Interestingly, nails exhibit continuous growth under physiological conditions and can fully regenerate upon removal. This chapter covers new discoveries of nail appendage biology, its growth regulation, and the mechanism of nail differentiation. Scientists have been intensely searching for stem cells in various organs in hopes of understanding and taking advantage of their regenerative abilities. Indeed, the skin is a complex organ containing a number of different “mini-organs,” skin appendages that are maintained by independent stem cell populations.

For the past several years, there have been active investigations and discussion about whether the nail organ alone possess stem cells that can regenerate the whole nail appendage or if other cells appear to contribute to nail regeneration. This chapter presents new discoveries about the coexistence of two independent populations of skin stem cells localized in the nail organ, with quite opposite cell cycle dynamics, namely a slow-cycling population of bifunctional nail proximal fold stem cells (NPFSCs) and fast-cycling nail stem cells (NSCs). In addition, their reciprocal dependence and interactions during nail organ regeneration have been discussed. Thus, nails contain a gradient of slow- to fast-cycling cells, with slow-cycling NPFCs and then more active cells in the intermediate zone (IZ) that separate them from highly proliferative stem cells in the nail proximal matrix.

We also present a new function of nail organ, specifically newly discovered NSCs in the nail proximal matrix and their adjacent progenitors in the nail distal matrix that contribute actively to nail differentiation and their surprising critical role in orchestrating digit regeneration in mammals. Moreover, stem cell isolation from ...

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