Seymour Gelfant

Aging: Noncycling Cells an Explanation

We have defined (1-5) three categories of potentially proliferating cells. The first is cycling cells that are actively moving through the cell cycle, G1 SG.M (where G1 and G, are gaps. S is the period of nuclear DNA synthesis, and NM is the period of mitosis). In addition there are two categories of noncycling cells, G1 blocked and G., blocked, which are capable of moving into the cell cycle upon specific stimuLlation. All three populations of cells can exist within the same tissue. However, their relative proportions and transitions vary with changing environment. physiological conditions, and age. Some of the phenomena explaining cell and tissuLe aging appear to be based upOIn transitions from cycling to noncycling cells (G, or GL blocked). In this article we present a model for viewing cellular aging in terms of these transitions. The model applies only to tissues capable of proliferation. It is supported both by our initial experimients and by resuLlts of others.

The cell cycle in psoriasis: a reappraisal

The current belief that the clinical manifestations of psoriasis (excessive scaling) are due to a twelve‐fold speeding up or shortening of the cell division cycle time of the germinative cells in psoriatic epidermis (from 457 to 37.5 h) is shown to be incorrect. A new concept is introduced‐that the germinative layer in human epidermis is composed of not one, but three separate and distinct populations of epidermal cells. First, there are cycling cells which are actively moving through the cell cycle. Then there are two categories of non‐cycling cells (blocked in the G1 or the G2 periods of the cell cycle) which are capable of moving into the proliferative pool upon specific stimulation. Thus, increased epidermal cell proliferation in active lesions of psoriasis would be brought about mainly by a recruitment or a release of the two categories of non‐cycling cells. The idea that germinative epidermal cells are primarily non‐cycling, leads to the suggestion of focusing attention on noncycling cells (rather than on cycling cells) for the control and treatment of psoriasis. It might be worthwhile considering treating psoriatic patients during periods of clinical remission‐with factors to keep the germinative cells in the non‐cycling state‐rather than during psoriatic flare up‐with cancer chemotherapy drugs.

On the existence of non‐cycling germinative cells in human epidermis in vivo and cell cycle aspects of psoriasis

Abstract. This report deals with the controversies of whether all germinative epidermal cells in human epidermis are in the cycling state and whether stimulated hyperproliferation of psoriatic epidermis is due to a shortening of the cell cycle time or to a recruitment of non‐cycling germinative epidermal cells. Experiments were performed on human subjects in vivo. Continuous infusion of [3H]thymidine for 8½ days indicated that 40% of germinative epidermal cells reside in the non‐cycling state. Proliferative stimulation by tape stripping indicated recruitment of non‐cycling (G0) germinative epidermal cells in both normal and psoriatic skin, and a prolongation (rather than a shortening) of cell cycle traverse in activated psoriatic epidermal cells.

Cycling ⇄ Noncycling Cell Transitions in Tissue Aging, Immunological Surveillance, Transformation, and Tumor Growth

Publisher Summary This chapter discusses the model for cell and tissue proliferation, which interrelates the problems of tissue aging, immunological surveillance, transformation, and tumor growth. The chapter illustrates diagrams that depict cycling and noncycling cell proliferative transitions as they apply to the problems of aging, immunological surveillance, transformation, and tumor growth. It also describes the cycling to noncycling cell transitions, which lead to the establishment of normal tissues composed of four major categories of cycling, noncycling G 1 -, G 0 -, and G 2 -blocked cells, which are arrested at different temporal and biochemical points in the G 1 and the G 2 periods of the cell cycle. Tissue proliferative aging and immunosenescence (age-related decline in immune function) are depicted as being caused by impaired release of noncycling cells to the proliferative cycling state. A primary tumor may arise from the immunological release and proliferation of preexisting, previously transformed dormant noncycling tumor cells, which had been held in restraint by immunological suppression.

Mitotic and Labelling Activity In Normal Human Epidermis In Vivo

Labelling and mitotic indices were studied in the epidermis of twenty‐eight young men. A mean labelling index of 5.5% was found from the whole study and a mean mitotic index of 0.06%. Mitotic index particularly was extremely variable; indices between 0.002 and 0.438% were found in individual biopsies. In the first two of three experiments in which mitotic index at 09.00 hours was compared with that at 15.00 hours, significant differences were found (15.00 hours > 09.00 hours by a factor of 2.6, P < 0.001). However, in the third such experiment no such difference was found, suggesting that the timing and occurrence of diurnal rhythms of mitotic activity may not be consistent in normal human epidermis. In the one experiment in which it was investigated, a significantly higher mitotic index was found at 21.00 hours compared to 09.00 and 15.00 hours. Labelling index did not vary significantly at 09.00, 15.00 or 21.00 hours. However, labelling index did show a significant pattern of change over a 12‐month period in two groups of subjects; peaks of labelling were seen in July and troughs in January. Very high ratios of labelled: mitotic cells were found, the median ratio for the whole study being ninety‐eight labelled: one mitotic cell. This finding supports the possibility that not all labelled cells subsequently go on to divide in normal human epidermis.

An attempt to use vincristine and colcemid to measure proliferative rates in normal human epidermis in vivo

A range of doses of vincristine (0.5–10 μg) or colcemid (5–100 μg) injected intradermally into normal volunteers failed to yield any significant accumulation of arrested mitoses. This was despite an apparently successful block of cells in metaphase by the highest three doses of each drug. Possible reasons for the failure to see accumulation are discussed. The results suggest that normal human epidermis is not a suitable system for application of the metaphase‐arrest technique using intradermal injection.

Psoriasis versus Cancer: Adaptive versus Iatrogenic Human Cell Proliferative Diseases

Publisher Summary This chapter presents a comparison between psoriasis and cancer and provides annotated diagrams that depict, describe, compare, and contrast the cycling⇆noncycling cell proliferative transitions as they apply to the problems of psoriasis and cancer in man. The major clinical aspects of psoriasis—that is, the original manifestation, remission, and relapse of active psoriasis—are explained in terms of recruitment and return of germinative epidermal cells to the cycling and noncycling states. Psoriasis is a disease of epidermal hyperplasia resulting in a faster epidermal cell transit to the stratum corneum and to excessive scaling, which is the main clinical disturbance in psoriasis. Cancer is a disease of the transformation of normal cells in a heritable manner and the establishment of invasive primary, secondary, and disseminated tumor growths. The chapter discusses the psoriatic proliferative responses and tumor proliferative responses to therapy.