Colony-forming human epidermal cells are heterogeneous in their capacity for sustained growth. Once a clone has been derived from a single cell, its growth potential can be estimated from the colony types resulting from a single plating, and the clone can be assigned to one of three classes. The holoclone has the greatest reproductive capacity: under standard conditions, fewer than 5% of the colonies formed by the cells of a holoclone abort and terminally differentiate. The paraclone contains exclusively cells with a short replicative lifespan (not more than 15 cell generations), after which they uniformly abort and terminally differentiate. The third type of clone, the meroclone, contains a mixture of cells of different growth potential and is a transitional stage between the holoclone and the paraclone. The incidence of the different clonal types is affected by aging, since cells originating from the epidermis of older donors give rise to a lower proportion of holoclones and a higher proportion of paraclones.

https://www.pnas.org/content/pnas/84/8/2302.full.pdf

Three clonal types of keratinocyte with different capacities for multiplication

Psoriatic skin is characterized by microvascular hyperpermeability and angioproliferation, but the mechanisms responsible are unknown. We report here that the hyperplastic epidermis of psoriatic skin expresses strikingly increased amounts of vascular permeability factor (VPF; vascular endothelial growth factor), a selective endothelial cell mitogen that enhances microvascular permeability. Moreover, two VPF receptors, kdr and flt-1, are overexpressed by papillary dermal microvascular endothelial cells. Transforming growth factor alpha (TGF-alpha), a cytokine that is also overexpressed in psoriatic epidermis, induced VPF gene expression by cultured epidermal keratinocytes. VPF secreted by TGF-alpha-stimulated keratinocytes was bioactive, as demonstrated by its mitogenic effect on dermal microvascular endothelial cells in vitro. Together, these findings suggest that TGF-alpha regulates VPF expression in psoriasis by an autocrine mechanism, leading to vascular hyperpermeability and angiogenesis. Similar mechanisms may operate in tumors and in healing skin wounds which also commonly express both VPF and TGF-alpha.

/pdf/overexpression-of-vascular-permeability-factor-vascular-24pe31ytwq.pdf

Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis

Transforming growth factor alpha (TGF-alpha) is produced by and required for the growth of epithelial cells and is angiogenic in vivo. Since epidermal hyperplasia and angiogenesis are hallmarks of psoriasis, TGF-alpha gene expression was analyzed in epidermal biopsies of normal and psoriatic skin. TGF-alpha messenger RNA and protein are much more abundant in lesional psoriatic epidermis than in normal-appearing skin of psoriatic patients or in normal epidermis. In contrast, messenger RNA levels of transforming growth factor beta 1 (TGF-beta 1), which inhibits epithelial cell growth, are not significantly different in normal, uninvolved, and lesional psoriatic epidermis. Thus, psoriatic epidermal hyperplasia may involve increased expression of a keratinocyte mitogen (TGF-alpha) rather than deficient expression of a growth inhibitor (TGF-beta 1).

https://science.sciencemag.org/content/sci/243/4892/811.full.pdf

Overexpression of transforming growth factor α in psoriatic epidermis

https://www.cell.com/cell/pdf/0092-8674(94)90383-2.pdf

Location of stem cells of human hair follicles by clonal analysis

Cytotoxic chemotherapy targets elements common to all nucleated human cells, such as DNA and microtubules, yet it selectively kills tumor cells. Here we show that clinical response to these drugs correlates with, and may be partially governed by, the pretreatment proximity of tumor cell mitochondria to the apoptotic threshold, a property called mitochondrial priming. We used BH3 profiling to measure priming in tumor cells from patients with multiple myeloma, acute myelogenous and lymphoblastic leukemia, and ovarian cancer. This assay measures mitochondrial response to peptides derived from proapoptotic BH3 domains of proteins critical for death signaling to mitochondria. Patients with highly primed cancers exhibited superior clinical response to chemotherapy. In contrast, chemoresistant cancers and normal tissues were poorly primed. Manipulation of mitochondrial priming might enhance the efficacy of cytotoxic agents.

/pdf/pretreatment-mitochondrial-priming-correlates-with-clinical-23tpkznzu2.pdf

Pretreatment Mitochondrial Priming Correlates with Clinical Response to Cytotoxic Chemotherapy

Cell Proliferation in Normal Epidermis

Cell kinetic basis for pathophysiology of psoriasis.

Skin biopsy specimens obtained from involved skin from sixteen patients with systemic and discoid lupus erythematosus were studied. Murine monoclonal antibodies with a biotin-avidin-horseradish peroxidase staining system were used. The findings consisted of (1) a marked reduction in the number of epidermal Langerhans cells defined by surface antigens, (2) reduced HLA-DR (Ia-like) antigens on the surface of dermal capillary endothelium, and (3) mononuclear cell infiltrates characterized by a predominance of helper T lymphocytes and an increase in the number of mononuclear phagocytic cells. B lymphocytes were rarely identified. The number of T lymphocytes within the dermis correlated inversely with both the number of HLA-DR-positive epidermal Langerhans cells (p

https://www.jaad.org/article/S0190-9622(86)70196-5/pdf

Immunopathology of cutaneous human lupus erythematosus defined by murine monoclonal antibodies.

Scanning acoustic microscopy of neoplastic and inflammatory cutaneous tissue specimens.

HeLa × keratinocyte hybrid cells have been used as immunogens to generate monoclonal antibodies against differentiation-specific antigens. A key feature of the experimental system is that the hybrid cells are undifferentiated in culture and yet terminally differentiate in the mouse. The properties of these cells allow one a facile approach to obtaining and characterizing monoclonal antibodies against differentiation-specific antigens. Use of hybrid cells derived from HeLa × differentiated cell fusions as immunogens should prove to be a general method for identifying differentiation-specific antigens from a variety of differentiated cell types.

https://cancerres.aacrjournals.org/content/canres/46/9/4759.full.pdf

Priscilla Ross

Papers

Cell Proliferation in Normal Epidermis

Cell kinetic basis for pathophysiology of psoriasis.

Immunopathology of cutaneous human lupus erythematosus defined by murine monoclonal antibodies.

Scanning acoustic microscopy of neoplastic and inflammatory cutaneous tissue specimens.

A Novel Approach for Obtaining and Identifying Monoclonal Antibodies That React with Differentiation-specific Antigens Using Human Hybrid Cells