Alexander Khalyavkin
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Local heterogeneity of basal cells of the epidermis
Izvestia Akademii Nauk SSSR. Seria Biologicheskaya. 5, 778-780, 1982.
(Bulletin of the USSR Academy of Sciences. Biology Series. Vol. 5, pp. 778-780, 1982)
Alexander Khalyavkin
In Russian: Локалная гетерогенность базальных клеток эпидермиса.
Khalyavkin Local Heterogeneity of Basal Epidermis Cells 82 5
Abstract:
We have critically analyzed the concept that posits local heterogeneity of basal cells of the epidermis, namely their separation into stem cells and cells that started differentiation. We show that the experimental data on which this concept is based, can be interpreted within the framework of the classical scheme of keratinocyte histogenesis, according to which all basal cells are stem cells and their heterogeneity with reference to several attributes can be related to their different stages within the cell cycle.
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A series of experimental data, obtained within the last years, indicated the presence of two different types of cells within the population of the basal cells of the epidermis, namely basal stem cells and basal cells committed to differentiation, which differ in their ability for proliferation and differentiation (Potten, Hendry, 1973; Krieg et al., 1974; Marks, 1976; Potten et al., 1979; Potten, 1981). The present article analyzes the justification for this concept which is proposed on the basis of experiments studying clonogenic properties of basal cells and their sensitivity to the effect of G1-Chalone (Potten, Hendry, 1973; Marks, 1976).
In radio-biological experiments studying clonogenicity of basal cells in the epidermis of irradiated animals, there was registered the number of colonies formed after certain times following different doses of radiation exposure. Under low doses, there were many surviving cells, the colonies merged and their number was impossible to determine. Therefore the initial number of clonogenic cells was estimated indirectly by extrapolating the data obtained to zero radiation dose, while taking into account the possibility of an initial shoulder in the dose-effect relation. The number of clonogenic basal cells, estimated this way, was much less than the general number of basal cells. This led to the hypothesis that only a part of basal cells are clonogenic stem cells, while the rest are their more differentiated progeny (Potten, Hendry, 1973). This concept was developed in the works studying the effects of exposure of basal cells to the endogenous tissue-specific inhibitor of proliferation – the epidermal G1-Chalone (Krieg et al., 1974, Marks, 1976). These experiments showed that the actively proliferating epidermis (neonatal skin, regenerating skin and skin subjected to tumor promoters) demonstrates reduced sensitivity to G1-Chalone as compared to normal adult epidermis. Within the framework of the concept under consideration, this was explained by suggesting that the basal cells of actively proliferating epidermis contain a larger proportion of stem cells presumably insensitive to the effect of G1-Chalone (Krieg, et al., 1974; Marks, 1976).
Thus, based on the different sensitivity to the influence of G1-Chalone and based on experiments studying colony formation in epidermis of irradiated animals, a concept was advanced suggesting the attribution of basal cells to two populations: stem cells-progenitors and their progeny committed to differentiation (Potten, Hendry, 1973; Marks, 1976). This means that, instead of the known histogenic series of stages of keratinocyte maturation (the basal cell → spinous cell → granular cell, etc.), the following modification of this scheme is proposed: the basal stem cell → the basal cell that started differentiation → spinous cell → granular cell, etc. This modified scheme is further supported by the data regarding colony formation of epidermal cells in culture. It is known that the number of colonies formed is much less than the number of seeded basal cells (Rheinwald, Green, 1977). This also seems to indicate that not all basal cells are clonogenic stem cells.
However, it is possible that the observed differences in the properties of basal cells are the results of other causes, namely the heterogeneity of their positioning within the cell cycle.
It is known that a part of basal cells is outside the mitotic cycle (Fukuda et al. 1978). This state is termed “proliferative rest” i.e. Phase G0 (Lajtha, 1963) or Phase R1 (Epifanova, Terskikh, 1968; Terskich, 1973). The rest of the cells undergo different stages of the mitotic cycle. Insofar as the resting cells are more resistant to external influences than the proliferating cells (Terskich, 1973), the dependence of the number of colonies formed on high doses of irradiation can reflect the radio-sensitivity of resting basal cells. Therefore the extrapolation of this dependence to the zero dose, taking into account the initial shoulder, gives the value equal to the number of basal cells that are found outside the mitotic cycle. Clearly, their number should be less than the general number of basal cells. This can also explain the different ability of basal cells for colony formation in culture. It is assumed that the signal for the transition of basal cells to the path of irreversible differentiation is their detachment from the dermo-epidermal boundary (Flaxman 1972). Therefore, when preparing their reseeding into culture, basal cells are detached from dermal substrate, a part of them, found in G0 state, begin irreversible differentiation and are unable to form colonies. The rest of the cells, found in the mitotic cycle, before transition to differentiation, must complete it. However, during the time of the cycle, their majority gets to precipitate in the culture vessel, attach to the appropriate substrate and therefore is able to form colonies. Hence, an increase of the time interval between the detachment of basal cells form dermal substrate and their placement in the culture on the feeder fibroblast layer, leads to a reduction in the number of colonies formed, while an increase of the proportion of proliferating cells of the epidermis raises this number (Rheinwald, Green, 1977).
In order to explain the mechanism of cell transition to the state of proliferative rest, it was suggested that the cells are affected by tissue-specific inhibitors of the mitotic cycle (Bullough, 1963, Lajtha, 1969). The cells can reside in the resting state for a prolonged time and enter the mitotic cycle under the influence of an inductive stimulus (Lajtha, 1969; Smith, Martin, 1973). It is assumed that at any time, under constant conditions, the mitotic cycle is entered by the same proportion of the remaining resting cells (Smith, Martin, 1973). Apparently, the proliferation starts in cells in which the stimulating signal prevails over the inhibiting signal. If assuming that the stationary distribution of resting cells according to the inhibiting signal value, created by the chalones, is nearly Gaussian bell-shaped curve, then the proportion of cells entering the mitotic cycle under the inductive stimulus will be determined by the area beneath the distribution curve, limited on the right by the inhibiting signal value, equal to the stimulating signal value (the inductive stimulus). The addition of chalones will shift the distribution to the right, hence the proportion of cells entering the cycle will diminish. The ratio of the proportion of cells entering the mitotic cycle after the addition of chalones to the proportion of cells entering the cycle without the addition of the chalone, reflects its inhibiting action. The lower this ratio, the more expressed is the chalone’s inhibiting action. These considerations explain why the inhibiting activity of the chalones is better expressed in a cell population subjected to the influence of a small inductive stimulus. Therefore there is no need to adduce the hypothesis about the larger proportion of stem cells presumably insensitive to the effect of chalones, in an actively proliferating population of basal cells. Also the very suggestion about the insensitivity of stem cells to chalones is quite vulnerable (Krieg et al. 1974; Marks 1976).
Thus the present analysis allows us to conclude that, despite the attraction of the concept that only a part of basal cells are stem cells, it would be premature to accept it as a final conclusion. This is because the experimental facts, lying at the foundation of that concept, can be explained by the heterogeneity of basal cells with reference to their position in the cell cycle.
In conclusion, we would like to note that the study of colony formation in a culture of epidermal cells, obtained from irradiated animals, would allow the evaluation of the real character of the dose-effect dependence under low irradiation doses. This could serve as one of the proofs or refutations for the correctness of the concept under consideration.
References:
Епифанова О.И., Терских В.В. Периоды покоя и активной пролиферации в жизненном цикле клетки. – Ж. Общ. Биол. 1968б т. 29. № 4, с. 392. (Epifanova O.I. Terskich V.V. Period of Rest and active proliferation in cell life cycle. Journal of General Biology – in Russian, vol. 29, no. 4, p. 392, 1968).
Терских В.В. Периоды покоя в нормальных и малигнизированных клетках. – В кн. Клеточный цикл. М. Наука 1973, с. 165. (Terskich V.V. Periods of rest in normal and malignant cells, in Cell Cycle, Nauka, Moscow, 1973, p. 165).
Bullough W.S. Analysis of the life cycle in mammalian cells. – Nature, 1963, v. 199, No. 4896, p. 859.
Flaxman B.A. Replication and differentiation in vitro of epidermal cells from normal skin and from benign (psoriasis) and malignant (basal cell cancer) hyperplasia. – In Vitro, 1972, v. 8, No. 3, p. 327.
Furuda M., Okamura K, Fujita S, Bohm M, Rohbach R, Sandritter W. The different stem cell populations in mouse epidermis and lingual epithelium. – Path. Res. Pract., 1978, v. 163, No. 3, p. 205.
Krieg L, Kuhlmann I, Marks F. Effect of tumor-promoting phorbol esters and acetic acid on mechanisms controlling DNA synthesis and mitosis (chalones) and on the biosynthesis of histidine-rich protein in mouse epidermis. – Cancer Res. 1974, v. 34, No. 11, p. 3135.
Lajtha L.G. On the concept of the cell cycle. – J. Cell Compar. Physiol., 1963, v. 60, No. 2, Suppl. 1, p. 143.
Lajtha L.G. Kinetic models of hemopoietic stem cell population. – Hemic cells in vitro, 1969, v. 4, p. 14.
Marks F. Epidermal growth control mechanisms hyperplasia, and tumor promotion in the skin. – Cancer Res. 1976, v. 36, No. 7, part 2, p. 2636.
Potten C. S. Cell replacement in epidermis (keratopoiesis) via discrete units of proliferativation. – Int. Ev. Cyt. 1981, v. 69, p. 271.
Potten C.S., Hendry J.H. Clonogenic cells and stem cells in epidermis. – Intern. J. Radiat. Biol, 1973, v. 24, No. 5, p. 537.
Potten C.S. Schofield R, Lajtha L.G. A comparison of cell replacement in bone marrow, testis and three regions of surface epithelium. – Biochem. Biophys. Acta, 1979, v. 560, No. 2, p. 281.
Rheinwald J.G. Green H. Epidermal growth factor and the multiplication of cultured human epidermal keratinocytes. – Nature, 1977, v. 265, No. 5593, p. 421.
Smith J.A., Martin L. Do cell cycle? – Proc Natl. Acad. Sci. USA, 1973, v. 70, No. 4, p. 1236.
Institute of Chemical Physical – The USSR Academy of Sciences, Moscow
Arrived to the editorial office
3.XI.1981
Khyalyavkin A.V.
The local heterogeneity of the basal cells of epidermis
Institute of Chemical Physics, Academy of Sciences of the USSR, Moscow
The critical analysis of the concept, postulating the subdivision of the basal cells of the epidermis into the stem cells and the cells at the beginning of the differentiation is given. It was shown that the experimental data, providing the basis of the concept, can be interpreted within the limits of the classical scheme of keratinocyte’s histogenesis, according to which all basal cells are know as stem cells, but their heterogeneity in a number of properties can be related with the different place in the cellular cycle. The experiment, the results of which can be used as the argument in favor of one of the alternative concepts, is suggested.
In Russian:
Локалная гетерогенность базальных клеток эпидермиса.
Khalyavkin Local Heterogeneity of Basal Epidermis Cells 82 5
УДК 576.321.34
Халявкин А.В.
Локальная гетерогенность базальных клеток эпидермиса.
Проведен критический анализ концепции, постулирующей локальную гетерогенность базальных клеток эпидермиса, которая заключается в подразделении их на стволовые клетки и клетки, приступившие к дифференцировке. Показано, что экспериментальные данные, лежащие в основе этой концепции, могут быть интерпретированы в рамках классической схемы гистогенеза кератиноцита, согласно которой все базальные клетки являются стволовыми, а их гетерогенность по ряду свойств может быть связаны с различным положением в клеточном цикле.
Ряд экспериментальных данных, полученных в последние годы, привел к представлении о наличии в популяции базальных клеток эпидермиса двух различных типов клеток – стволовых базальных клеток и коммтированных к дифференцировке (Potten, Hendry, 1973; Krieg et al. 1974; Makrs, 1976; Potten et al. 1979; Potten 1981). В настоящем сообщении анализируется обоснованность этой концепции, высказанной на основе экспериментов по изучению клоногенных свойств базальных клеток и их чувствительности к действию G1-кейлона (Potten, Hendry, 1973; Marks, 1976).
В радиобиологических экспериментах по изучению клоногенности базальных клеток в эпидермисе облученных животных регистрировалось число колоний, образовавшихся спустя определенное время после действия разных доз облучения. При низких дозах выживших клеток было много, колонии сливались, и их количество определить было невозможно. Поэтому начальное число клоногенных клеток оценивалось косвенно экстраполяцией полученных данных к нулевой дозе облучения с учетом возможного начального плеча на зависимости доза – эффект. Оцененное таким образом число клоногенных базальных клеток оказалось гораздо меньше общего числа базальных клеток. Это дало повод предположить, что только часть базальных клеток является стволовыми (Potten, Hendry, 1973). Данная концепция получила развитие в работах по изучению действия на базальные клетки эндогенного тканеспецифического ингибитора пролиферации – эпидермального G1-кейлона (Krieg et al., 1974, Marks, 1976). В этих опытах было показано, что активно пролиферирующий эпидермис (неонатальная кожа, регенерирующая кожа и кожа, находящаяся под воздействием опухолевого промотера) проявляет пониженную чувствительность к действую G1-кейлона в сравнении с нормальным эпидермисом взрослого. В рамках рассматриваемой концепции это объяснялось тем, что базальные клетки активно пролиферирующего эпидермиса содержат большую долю стволовых клеток, предположительно нечувствительных к действию G1-кейлона (Krieg et al., 1974, Marks, 1976).
Таким образом, на основании различной чувствительности к действию G1-кейлона и на основании экспериментов по изучению колониеобрзования в эпидермисе облученных животных была выдвинута концепция о принадлежности базальных клеток к двум популяциям: стволовых клеток-предшественников и их потомков, коммитированных к дифференцировке (Potten, Hendry, 1973 Marks, 1976). Это означает, что вместо известного гистогенетического ряда стадий созревания кератиноцита (базальная клетка ->шиповатая->зернистая и т.д) предполагается следующая модификация этой схемы: базальная стволовая клетка –< базальная клетка, приступившая к дифференцировке –> шиповатая –> зернистая и т.д. В пользу такой модифицированной схемы можно привести и данный по колониеобразованию эпидермальных клеток в культуре. Известно, что число образуемых колоний гораздо меньше числа высеваемых базальных клеток (Rheinwald, Green, 1977). Это как будто бы тоже говорит за то, что не все базальные клетки являются стволовыми клоногенными клетками.
Однако возможно, что наблюдаемые различия в свойствах базальных клеток являются следствием других причин, а именно гетерогенность по положению в клеточном цикле.
Известно, что часть базальных клеток находится вне митотического цикла (Fukuda et al, 1978). Это состояние называется пролиферативным покоем, фазой G0 (Lajtha, 1963) или фазой R1 (Епифанова, Терских, 1968; Терских, 1973). Остальные клетки проходят различные стадии митотического цикла. Поскольку покоящиеся клетки более резистентны к внешним воздействиям, чем пролифирирующие (Терских, 1973), зависмость числа образованных колоний от высоких доз облучения может отражать радиочувствительность покоящихся базальных клеток. Поэтому экстраполяция этой зависимости к нулевой дозе с учетом начального плеча даст величину, равную числу базальных клеток, находящихся вне митотического цикла. Ясно, что их число должно быть меньше общего числа базальных клеток. Этим же можно объяснить и различную способность базальных клеток к колониеобразованию в культуре. Считается, что сигналом для перехода базальных клеток на пусть необратимой дифференцировки является их отрыв от дермо-эпидермальной границы (Flaxman, 1972). Поэтому, когда для подготовки к пересеву их в культуру базальные клетки отделяются от дермальной подложки, часть из них, находящаяся в состоянии G0, начинает необратимую дифференцировку и не способна образовывать колонии. Остальные клетки, находящиеся в митотическом цикле, до перехода в дифференцировку должны завершить его. Однако за время прохождения цикла большинство из них успевает осесть в сосуде для культивирования, закрепиться на соответствующем субстрате и поэтому способно образовывать колонии. Таким образом, увеличение интервала времени между отделением базальных клеток от дермальной подложки и помещением их в культуру на фидерный слой фибробластов приводит к уменьшению количества образуемых колоний, а повышение доли пролиферирующих клеток эпидермиса увеличивает это количество (Rheiwald, Green, 1977).
Для объяснения механизма перехода клеток в состоянии пролиферативного покоя было предложено, что на клетки действуют тканеспецифические ингибиторы митотического цикла (Bullough, 1963; Lajtha, 1969). Клетки могут находиться в периоде покоя длительное время и вступать в митотический цикл под влиянием индуктивного стимула (Lajtha, 1969; Smith, Martin, 1973). Считается, что каждый момент времени при постоянных условиях в митотический цикл вступает одна и та же доля оставшихся покоящихся клеток (Smith, Martin, 1973). Видимо, начинают пролиферацию те из них, у которых стимулирующий сигнал превалирует над ингибирующим. Если предположить, что стационарное распределение покоящихся клеток по величине ингибирующего сигнала, создаваемого кейлоном, близко к колоколообразной кривой, то доля клеток, вступающих в митотический цикл под воздействием индуктивного стимула, определится площадью под кривой распределения, ограниченной справа величиной ингибирующего сигнала, равной величине стимулирующего сигнала (индуктивного стимула). Добавление кейлона сместит распределение вправо, поэтому доля клеток, входящих в цикл, уменьшится. Отношение доли клеток, входящих в митотический цикл после добавления кейлона к доле клеток, входящих в митотический цикл после добавления кейлона к доле клеток, входящих в цикл без добавления кейлона, отражает его ингибирующее действие. Чем это отношение ниже, тем ингибирующее действие кейлона выражено больше. Из этих рассуждений видно, почему ингибирующая активность кейлона лучше проявляется в популяции клеток, находящихся под воздействием небольшого индуктивного стимула. Поэтому нет никакой необходимости привлекать гипотезу о большей доле стволовых клеток, предположительно не чувствительных к действию кейлона, в активно пролиферирующей популяции базальных клеток. Достаточно уязвимо и само предположение о нечувствительности стволовых клеток к кейлону (Krieg et al., 1974; Marks, 1976).
Таким образом, проведенный анализ позволяет заключить, что, несмотря на привлекательность концепции о том, что только часть базальных клеток является стволовыми, окончательность такого вывода была бы преждевременной. То следует из того, что экспериментальные факты, на которых построена данная концепция, могут объясняться гетерогенностью базальных клеток по их положению в клеточном цикле.
В заключение отметим, что изучение колониеобразования в культуре эпидермальных клеток, взятых от облученных животных, позволило бы судить об истинном характере зависимости доза – эффект в области низких доз облучения. Это могло послужить одним из доказательств или опровержения справедливости рассматриваемой концепции.
Литература
Епифанова О.И., Терских В.В. Периоды покоя и активной пролиферации в жизненном цикле клетки. – Ж. Общ. Биол. 1968б т. 29. № 4, с. 392.
Терских В.В. Периоды покоя в нормальных и малигнизированных клетках. – В кн. Клеточный цикл. М. Наука 1973, с. 165.
Bullough W.S. Analysis of the life cycle in mammalian cells. – Nature, 1963, v. 199, No. 4896, p. 859.
Flaxman B.A. Replication and differentiation in vitro of epidermal cells from normal skin and from benign (psoriasis) and malignant (basal cell cancer) hyperplasia. – In Vitro, 1972, v. 8, No. 3, p. 327.
Furuda M., Okamura K, Fujita S, Bohm M, Rohbach R, Sandritter W. The different stem cell populations in mouse epidermis and lingual epithelium. – Path. Res. Pract., 1978, v. 163, No. 3, p. 205.
Krieg L, Kuhlmann I, Marks F. Effect of tumor-promoting phorbol esters and acetic acid on mechanisms controlling DNA synthesis and mitosis (chalones) and on the biosynthesis of histidine-rich protein in mouse epidermis. – Cancer Res. 1974, v. 34, No. 11, p. 3135.
Lajtha L.G. On the concept of the cell cycle. – J. Cell Compar. Physiol., 1963, v. 60, No. 2, Suppl. 1, p. 143.
Lajtha L.G. Kinetic models of hemopoietic stem cell population. – Hemic cells in vitro, 1969, v. 4, p. 14.
Marks F. Epidermal growth control mechanisms hyperplasia, and tumor promotion in the skin. – Cancer Res. 1976, v. 36, No. 7, part 2, p. 2636.
Potten C. S. Cell replacement in epidermis (keratopoiesis) via discrete units of proliferativation. – Int. Ev. Cyt. 1981, v. 69, p. 271.
Potten C.S., Hendry J.H. Clonogenic cells and stem cells in epidermis. – Intern. J. Radiat. Biol, 1973, v. 24, No. 5, p. 537.
Potten C.S. Schofield R, Lajtha L.G. A comparison of cell replacement in bone marrow, testis and three regions of surface epithelium. – Biochem. Biophys. Acta, 1979, v. 560, No. 2, p. 281.
Rheinwald J.G. Green H. Epidermal growth factor and the multiplication of cultured human epidermal keratinocytes. – Nature, 1977, v. 265, No. 5593, p. 421.
Smith J.A., Martin L. Do cell cycle? – Proc Natl. Acad. Sci. USA, 1973, v. 70, No. 4, p. 1236.
Институт химической физики АН СССР
Москва
Поступила в редакцию
3.XI.1981
Khyalyavkin A.V.
The local heterogeneity of the basal cells of epidermis
Institute of Chemical Physics, Academy of Sciences of the USSR, Moscow
The critical analysis of the concept, postulating the subdivision of the basal cells of the epidermis into the stem cells and the cells at the beginning of the differentiation is given. It was shown that the experimental data, providing the basis of the concept, can be interpreted within the limits of the classical scheme of keratinocyte’s histogenesis, according to which all basal cells are know as stem cells, but their heterogeneity in a number of properties can be related with the different place in the cellular cycle. The experiment, the results of which can be used as the argument in favor of one of the alternative concepts, is suggested.
Локалная гетерогенность базальных клеток эпидермиса.
Khalyavkin Local Heterogeneity of Basal Epidermis Cells 82 5
—–
Epidermal homeostasis and the problem of psoriasis
Izvestia Akademii Nauk SSSR. Seria Biologicheskaya. 1, 156-159, 1982.
(Bulletin of the USSR Academy of Sciences. Biology Series. Vol. 1, pp. 156-159, 1982)
Alexander Khalyavkin
In Russian: Эпидермальный Гомеостаз и Проблема Псориаза
Khalyavkin Epidermal Homeostasis 82 1
Abstract
We consider a qualitative model of epidermal homeostasis, based on literature data. It is assumed that heterogeneous mitotic activity of the basal layer is responsible for the wave-like form of the dermo-epidermal boundary and is related to the specifics of the position of sub-epidermal lymphatic capillaries. We consider the conditions under which an increase of mitotic activity leads to an abnormally high transition of cells to differentiation, but only in some zones of the basal layer. We show that such an imbalance of cell streams can lead to the main histological signs of psoriasis, namely acanthosis, papillomatosis and parakeratosis.
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Psoriasis is a widespread chronic disease of the skin with uncertain etiology and pathogenesis (Mordovzev, 1977; Skripkin, 1980; Flaxman et al. 1979 and others). The main signs of the disease are increased squamous appearance of the surface layers of the epidermis and their immaturity (parakeratosis), the anomalously high mitotic activity of the keratinocytes, the elongation of epidermal outgrowths accompanied by in-growth into the epidermis of dermal papillae along with thinning of the above-papillae areas of the epidermis (acanthosis and papillomatosis) and some others. The existing methods of therapy do to produce a lasting effect. The absence of an analogous disease in animals is a serious drawback for the experimental study of this pathology. The matter is further complicated by the fact that the epidermal homeostasis itself, whose impairment is assumed in psoriasis, has not been studied sufficiently (Mikhailv 1979, Skerrow1978). Therefore the current work makes an attempt to consider, based on the exiting data and concepts, a qualitative model of epidermal homeostasis and its impairment, possibly leading to psoriasis.
The surface of normal epidermis is the cornea, the end product of the skin epithelium differentiation. During the life course, the cells of the upper layers of the cornea are gradually shed and gradually replaced by mature cells from lower differentiating layers. These, in turn, are replaced by cells of the basal layer making a transition toward differentiation. The replenishment of the population of basal stem cells takes place thanks to their proliferation.
The profile of the epidermis at the border with the dermis is a wave-like line. The degree of undulation in different parts of the skin varies greatly, in correlation with the thickness of the epidermis and mitotic activity (Bullough, Deol, 1975). The proliferative activity of the basal layer is maximal at the basis of epidermal outgrowths. At a greater distance from these zones, the activity gradually decreases, reaching the minimal values at the basal cells, found above the dermal papillae (Flaxman, 1972; Fukuda et al. 1978). The reason for this is unknown. Possibly, the proliferative zones concentrate clonogenic cells, whose existence was hypothesized by Potten (Potten, Hendry, 1973), or non-committed stem cells insensitive to the action of G1-Chalone, posited by Marks (Marks 1976). It was also suggested that the localization of proliferative and non-proliferative zones is related to the specific location of blood vessels in the underlying derma (Fukuda et al. 1978). However, apparently, the heterogeneous mitotic activity of the basal layer is not related to the underlying blood vascular net. This follows from the fact that the sub-epidermal plexus of blood capillaries repeats the contours of the dermo-epidermal boundary. In contrast to blood capillaries, the blind outgrowths of lymphatic capillaries reach only to the basis of epidermal outgrowths (Nadezhdin, 1951). Therefore the humoral factors, found in the lymphatic vessels, unlike mitogens carried by the blood stream, can stimulate the proliferation of basal cells located mainly in the immediate proximity of the expanded ends of lymphatic capillaries. Perhaps this is what causes the heterogeneous mitotic activity of the basal layer. The presumed mitogens circulating in the lymphatic system may be the hypothetical “mesenchymal factor” (Bullough, Deol, 1975) or normal anti-tissue antibodies which are dedicated to tissue-specific stimulation of proliferation, according to several authors (Piatnizky, Makhlin, 1969, Babaeva, 1972; Khalyavkin 1975; Burwell, 1963). Healthy persons show the presence of normal anti-epidermal auto-antibodies, while psoriasis patients show their increased amounts (Beutner et al. 1977; Krogh, 1977). Even though in these and other studies, the main focus is on auto-antibodies to the surface layer of the epidermis, Krogh does not exclude the possibility that increased amounts of auto-antibodies to the growth layer can be the cause of its enhanced proliferation as observed in psoriasis (Krogh, 1977). It should be noted that for the first time such a concept was expressed in a theoretical work dedicated to the problem of psoriasis, already in 1965 (Burch, Rowell, 1965). In any case, whatever the actual cause for the heterogeneous mitotic activity of the basal cells, found in different locations of the dermo-epidermal boundary, it can also be the cause for the wave-like appearance of this boundary. Indeed, normally the speed of migration for cells transiting to differentiation from various locations of the basal layer should be balanced in such a way that such cells should reach the skin surface simultaneously. The mechanism of cell migration into the upper layers of the epidermis is little known (Skerrow, 1978). It may be assumed that the probability of transition to differentiation and therefore the starting speed of migration depend on dermo-epidermal adhesion and local inter-cellular pressure, created by mitotic activity (Iversen et al. 1968; Bullough, Deol, 1975). It is assumed that the dermo-epidermal adhesion is maximal for the basal cells found in the mitotic cycle, and minimal for the cells found in late G1 phase (apparently in G0 phase), therefore it is those cells that are most easily pushed toward differentiation (Iversen et al, 1968; Bullough, Deol, 1975). Therefore, for basal cells found in G0 phase, the probability to transit to differentiation and the starting speed of migration is the highest in places of maximal mitotic activity. When distancing from such places, the initial speeds of migration should decrease. Possibly, this is why the profile of the dermo-epidermal boundary is so convoluted that cells migrating upward with different average speed pass different distances, so that during the differentiation time Td they should reach about the same plane, which is the lower boundary of the cornea layer. An increase of average mitotic activity should and normally does lead to a more or less proportional increase of the maximal and minimal speeds of migration, and therefore to the thickening of the epidermis and greater convolution of the dermo-epidermal boundary. A significant increase in the average mitotic activity can result in a situation when the force of inter-cellular pressure, acting on the basal cells located at the basis of epidermal outgrowths, will exceed the maximal force of adhesion of cells with the underlying derma. Then the basal cells, found in the mitotic cycle and located in places of maximal inter-cellular pressure, under its effect will be either completely expelled toward differentiation, or more likely will change their orientation. The change of orientation can lead to the transformation of “horizontal” symmetrical mitoses into asymmetrical “vertical” ones, whose percentage increase under increased proliferation has been noted in the literature (Pinkus, Hunger, 1966; Duffill et al. 1977; Bullough, Mitrani, 1978). The proportional increase of the maximal and minimal speeds of migration implies a coordination of the action of two sub-epidermal humoral systems – the lymphatic and the blood systems. If there is no such coordination for some reason, there may emerge a situation when rapid increase of mitotic activity of basal cells located at the basis of epidermal outgrowths will not be accompanied by a proportional increase of this activity in basal cells located above the dermal papillae. This will lead to a disproportional elongation of epidermal outgrowths (acanthosis and papillomatosis). Such an elongation of outgrowths also means the increase of its basal cells. Since in this case this increase cannot take place at the expense of replication of cells found in the zones of maximal proliferation, where mitoses are asymmetrical, then it proceeds at the expense of cells in other zones. This should lead to a decline of transition to differentiation from these zones, and therefore to a shortening of the thickness of epidermis above the dermal papillae, exacerbating papillomatosis. Acanthosis and papillomatosis are the main histological signs of psoriasis alongside with parakeratosis or the immaturity of the surface layer. It is possible that parakeratosis is also the result of imbalance of cellular streams – a drastic increase of the maximal migration without a proportional increase of the minimal speed. Indeed, despite the significant elongation of epidermal outgrowths, the speed of migration is so large that the lower boundary of the cornea layer, formed above dermal papillae (Flaxman 1972), is reached by cells that transited to differentiation from the bottom of the epidermal outgrowth at a time significantly smaller than Td. During that time, judging form morphological and biochemical data, they do not mature even to the stage of granular cells. The increased amount of auto-antibodies to the surface layer of the epidermis, observed in psoriasis, according to some authors (Beutner et al. 1977; Krogh, 1977) facilitates the stratification of this immature layer, which normally has quite strong inter-cellular adhesion (Skerrow, 1978).
In the early stages of ontogenesis, when the biosynthesis of antibodies is still low, and the blind outgrowths of the lymphatic capillaries are not pronounced (Nadezhdin, 1951), the leading role in the control of proliferation may be played by humoral factors carried by the blood stream and equally available for all basal cells. Therefore the mitoses are distributed quite homogeneously, which can explain the smooth profile of epidermis in the new born and the low incidence of psoriasis at this age.
Thus, the present literature analysis allows us to conclude that the lack of coordination of sub-epidermal humoral systems accompanied by increased mitotic activity of keratinocytes can lead to an impairment of epidermal homeostasis and the emergence of the main signs of psoriasis.
References
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Institute of Chemical Physics. USSR Academy of Sciences. Msocw.
Arrived at the Editorial Office. 10. II. 1981.
Original abstract:
Khalyavkin A.V. The Epidermal homeostasis and the problem of psoriasis
Institute of Chemical Physics, Academy of Sciences of the USSR, Moscow
It was stated that the irregular mitotic activity of the basal layer is responsible for the wavy character of the dermo-epidermal borderline and related by the specificity of the subepidermal lymphatic capillaries’ distribution. On the basis of the literature data’s analysis the conclusion is made that the non-co-ordination of the action of the subepidermal human systems, aimed at the increase of the mitotic activity of the keratinocytes can lead to the disturbances in the epidermal homeostasis and appearance of acanthosis, papillomatosis and parakeratosis in the psoriasis development.
In Russian: Эпидермальный Гомеостаз и Проблема Псориаза
Khalyavkin Epidermail Homeostasis 82 1
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Censor-Growth Model and Immunity
Censor-Growth Model and Immunity ORIGINAL 1975
Halyavkin-Censor Growth Model and Immunity-Thymus
ИЗВЕСТИЯ АКАДЕМИИ НАУК ГССР Серия биологическая, т. 1, № 5, 6, 1975
КРАТКИЕ СООБЩЕНИЯ
УДК 577.95
ТЕОРЕТИЧЕСКАЯ БИОЛОГИЯ
ЦЕНЗОРНО-РОСТОВАЯ МОДЕЛЬ И ИММУНИТЕТ* А. В. Халявкин
Институт физиологии АН ГССР, Тбилиси Поступила в редакцию 10.10.1975
CENSOR-GROWTH MODEL AND IMMUNITY
- V. HALYAVKIN
Institute of Physiology, Georgian Academy of Sciences, Tbilisi. USSR Summary
A model is offered according to which the immunological phenomena are соnsidered not as the obligatory defense mechanisms, but as a particular case of the mechanism of specific stimulation of mitosis.
In Russian: Ц Е Н З О Р Н О – Р О С Т О В А Я М О Д Е Л Ь И И М М У Н И Т Е Т
Censor-Growth Model and Immunity
Censor-Growth Model and Immunity ORIGINAL 1975
Halyavkin-Censor Growth Model and Immunity-Thymus
