Plasticity of rodent and human hair follicle dermal cells: implications for cell therapy and tissue engineering.

The dermal components of the hair follicle exhibit a number of stem cell properties, including regenerative potential, roles in wound healing and the ability to produce a functional dermis. Here we examine the stem cell phenomenon of plasticity, focusing on recent observations of in vitro plasticity of dermal papilla and sheath cells, including previously unpublished data of neuronal-like differentiation. We then briefly address the implications of the stem cell potential of hair follicle dermal cells for the field of tissue engineering.

Cultured human and rat tooth papilla cells induce hair follicle regeneration and fiber growth.

The mesenchymal-epithelial interactions that characterize the early stages of tooth and hair follicle morphogenesis share certain similarities, and there is increasing evidence that mesenchymal cells derived from both mature structures retain interactive and stem cell-like properties. This study aimed to gauge the cross-appendage inductive capabilities of cultured tooth dental papilla (or pulp) cells from different species and ages of donor. Adult human and juvenile rat tooth papilla cells were implanted into surgically inactivated hair follicles within two different microenvironments. The human cells interacted with follicle epithelium to regenerate new end bulbs and create multiple differentiated hair fibers. Rodent tooth dental cells also induced new epithelial matrix structures and stimulated de novo hair formation. However, in many instances they also elicited mineralization and bone formation, a phenomenon that appeared to relate to their donor's age; the type of tooth of origin; and the host environment. Taken together, this study reveals that cultured dental papilla cells from postnatal mammals (adult, juvenile, and newborn) retain inductive molecular signals that must be common to both hair and teeth follicles. It highlights the stem cell-like qualities and morphogenetic abilities of tooth and hair follicle cells from mature humans, and their capacity for cross-appendage and interspecies communication and interaction. Besides the developmental implications, the present findings have relevance for stem cell biology, hair growth, tissue repair, and other biotechnologies. Moreover, the critical importance of considering the local microenvironment in which different cells/tissues are naturally or experimentally engineered is firmly demonstrated.

The lanceolate hair rat phenotype results from a missense mutation in a calcium coordinating site of the desmoglein 4 gene.

Desmosomal cadherins are essential cell adhesion molecules present throughout the epidermis and other organs, whose major function is to provide mechanical integrity and stability to epithelial cells in a wide variety of tissues. We recently identified a novel desmoglein family member, Desmoglein 4 (Dsg4), using a positional cloning approach in two families with localized autosomal recessive hypotrichosis (LAH) and in the lanceolate hair (lah) mouse. In this study, we report cloning and identification of the rat Dsg4 gene, in which we discovered a missense mutation in a naturally occurring lanceolate hair (lah) rat mutant. Phenotypic analysis of lah/lah mutant rats revealed a striking hair shaft defect with the appearance of a lance head within defective hair shafts. The mutation disrupts a critical calcium binding site bridging the second and third extracellular domains of Dsg4, likely disrupting extracellular interactions of the protein.

Hair follicle dermal cells differentiate into adipogenic and osteogenic lineages.

The adult hair follicle dermal papilla (DP) and dermal sheath (DS) cells are developmentally active cell populations with a proven role in adult hair follicle-cycling activity and unique inductive powers. In stem cell biology, the hair follicle epithelium has recently been the subject of a great deal of investigation, but up to now, the follicle dermis has been largely overlooked as a source of stem cells. Following the sporadic appearance of muscle, lipid and bone-type cells in discretely isolated follicle DP and DS cell primary cultures, we demonstrated that cultured papilla and sheath cell lines were capable of being directed to lipid and bone differentiation. Subsequently, for the first time, we produced clonal DP and DS lines that had extended proliferative capabilities. Dye exclusion has been reported to be an identifying feature of stem cells; therefore, clonal papilla and sheath lines with differing capacity to exclude rhodamine 123 were cultured in medium known to induce adipocyte and osteocyte differentiation. Both DS- and DP-derived clones showed the capacity to make lipid and to produce calcified material; however, different clones had varied behaviour and there was no obvious correlation between their stem cell capabilities and dye exclusion or selected gene expression markers. As a highly accessible source, capable of being discretely isolated, the follicle has important potentially as a stem cell source for tissue engineering and cell therapy purposes. It will also be interesting to compare follicle dermal stem cell properties with the broader stem cell capabilities discovered in skin dermis and investigate whether, as we believe, the follicle is a key dermal stem cell niche. Finally, the discovery of stem cells in the dermis may have implications for certain pathologies in which abnormal differentiation occurs in the skin.

Genes that are differentially expressed in rat vibrissa follicle germinative epithelium in vivo show altered expression patterns after extended organ culture.

Hair growth depends on maintenance of signalling between the dermal papilla and the germinative epithelium (GE), from which the differentiated layers of the hair fibre originate. Because no molecular studies have been reported which concentrate specifically on GE cells either in vivo or in vitro, we prepared a cDNA library enriched for messages which were highly expressed in GE cells to identify genes that may be involved in hair growth control. Of 35 subtracted library clones sequenced, 23 shared extensive homology with previously determined cDNA sequences, including LEF-1 and id4. Hair follicle organ culture models are often used to investigate the molecular basis of hair growth, although hair growth arrest occurs relatively rapidly in vitro. As an indicator of their role in follicle activities, we compared the expression of GE-specific clones in different regions of freshly isolated vibrissa follicles, with the corresponding regions of growth arrested, cultured follicles. Changes in the expression of some of these clones indicates that they could be related to fundamental cellular activities in the follicle. A library enriched for GE-specific clones therefore provides a useful source of candidate molecules for studies of follicular epithelial cell behaviour, both in vivo and in vitro.