Skin Barrier Health: Regulation and Repair of the Stratum Corneum and the Role of Over-the-Counter Skin Care

The epidermis is primarily made up of keratinocytes, in addition to melanocytes and Langerhans cells. It consists of four layers: the basal layer, spinous layer, granular layer, and cornified layer, which is also known as the stratum corneum. It takes approximately 28 days for a keratinocyte to migrate and differentiate from the basal layer and ultimately be shed from the surface stratum corneum.¹ The keratinocyte is derived from stem cells of the basal layer, the bottom-most layer of the epidermis. Keratinocytes of the basal layer are the only viable cells of the epidermis. As these cells migrate and differentiate, they lose the ability to undergo mitosis. These specialized cells first arise from ectodermal tissues during the first few weeks of fetal life. Keratinocytes also express cytoskeletal proteins called keratins, which always form pairs with an acidic and basic subtype.¹ These proteins have structural and hygroscopic functions and also play a role in migration and cell differentiation.

As the keratinocyte migrates upwards, they differentiate into spinous layer cells, which are characterized by a more polyhedral shape and the expression of proteins called desmosomes. These proteins connect keratinocytes to each other. The formation of these desmosomal proteins is dependent on calcium dependent enzymes.¹ For these enzymes to function, the calcium gradient must increase in concentration towards the upper layers of the epidermis, facilitated by the expression of ATP-dependent calcium pumps, ATP2A2 and ATP2C1, which are mutated in Darier and Hailey-Hailey disease, respectively. As will be discussed below, this calcium gradient is crucial for differentiation of the keratinocyte as it migrates upwards.

Above the spinous layer is the granular layer, characterized by the keratohyaline granules, which consist of proteins such as profilaggrin, loricrin, involucrin, and envoplakin, that will later play a role in the formation of the cornified envelope.¹ Also unique to the granular layer are the lamellar granules, which are secretory organelles, derived from the Golgi apparatus.¹ These carry lipid products that will form the intercellular lipid content of the stratum corneum.^1,2

The transition from the granular layer to the stratum corneum marks a point of dramatic change as keratinocyte degradation takes place leading the differentiation of these cells into corneocytes. The nucleus, organelles, and plasma membrane are lost during this phase.¹ The contents of the keratohyaline granules are released and the profilaggrin proteins are degraded into individual filaggrin monomers by a calcium-dependent enzyme.1,2 These filaggrin monomers then bind with the keratin cytoskeletal proteins, preventing further breakdown of filaggrin until the setting of corneocyte dehydration occurs where it is further degraded by capase-14 and other enzymes into amino acids and amino acid derivatives that are needed to maintain moisturization.^2,3 Of note, urocanic acid, a breakdown product of filaggrin, also plays a crucial role as protection against UV radiation.3 Filaggrin, with the other keratohyaline granule proteins, are then assembled into the cornified envelope by enzymes called transglutaminases, which are calcium-dependent and serve to give physical structure to the corneocyte.¹ During this phase, the lamellar granules are also extruded into the intercellular space and the lipid contents then form the stacked lipid bilayers, which permeate the space between corneocytes.