Immunology of tissue homeostasis, ovarian cancer growth and regression, and long lasting cancer immune prophylaxis - review of literature.

Data on the substantial physiological role of the immune system in the organism's ability to manage proper differentiation and function of normal tissues (tissue homeostasis), and detailed causes of the immune system's essential role for the in-vivo stimulation of cancer growth, are severely lacking. This results in a lack of effective cancer immunotherapy without adverse events, and in the lack of long-lasting cancer immune prophylaxes, particularly in ovarian cancers. Elimination of blood auto-antibodies blocking anti-cancer T cell effectors by intermittent moderate doses of cyclophosphamide, facilitation of the immune system reactivity against alloantigens of cancer cells by two subsequent blood transfusions, and augmentation of anticancer immunity by weekly intradermal injections of bacterial toxins, caused during the subsequent treatment-free period, lasting for two to four weeks, regression of inoperable epithelial ovarian cancers and regeneration of the tremendously metastatically altered abdominal tissues into normal healthy conditions without multivisceral cytoreductive surgery, which can result in life-threatening consequences.

Involvement of blood mononuclear cells in the infertility, age-associated diseases and cancer treatment.

Blood mononuclear cells consist of T cells and monocyte derived cells. Beside immunity, the blood mononuclear cells belong to the complex tissue control system (TCS), where they exhibit morphostatic function by stimulating proliferation of tissue stem cells followed by cellular differentiation, that is stopped after attaining the proper functional stage, which differs among various tissue types. Therefore, the term immune and morphostatic system (IMS) should be implied.

From cellular to chemical approach for acute neural and alternative options for age-induced functional diseases.

Endogenous "stem cell niche" (SCN) accompanying vessels contains immune system components which in vivo determine differentiation of multi potent stem cells toward proper cell types in given tissue. Combinations of sex steroids may represent novel chemical approach for neuronal areas of regenerative medicine, since they cause transformation of vascular smooth muscle stem cells into differentiating neuronal cells. Circulating sex steroids are present during pregnancy and can be utilized where needed, when various embryonic/fetal tissues develop from their stem cells.

Novel methods of treating ovarian infertility in older and POF women, testicular infertility, and other human functional diseases.

In vitro maturation (IVM) and in vitro fertilization (IVF) technologies are facing with growing demands of older women to conceive. Although ovarian stem cells (OSCs) of older women are capable of producing in vitro fresh oocyte-like cells (OLCs), such cells cannot respond to IVM and IVF due to the lack of granulosa cells required for their maturation. Follicular renewal is also dependent on support of circulating blood mononuclear cells.

Immunoregulation of follicular renewal, selection, POF, and menopause in vivo, vs. neo-oogenesis in vitro, POF and ovarian infertility treatment, and a clinical trial.

The immune system plays an important role in the regulation of tissue homeostasis ("tissue immune physiology"). Function of distinct tissues during adulthood, including the ovary, requires (1) Renewal from stem cells, (2) Preservation of tissue-specific cells in a proper differentiated state, which differs among distinct tissues, and (3) Regulation of tissue quantity. Such morphostasis can be executed by the tissue control system, consisting of immune system-related components, vascular pericytes, and autonomic innervation.

Ovarian stem cell niche and follicular renewal in mammals.

Stem cell niche consists of perivascular compartment, which connects the stem cells to the immune and vascular systems. During embryonic period, extragonadal primordial germ cells colonize coelomic epithelium of developing gonads. Subsequently, ovarian stem cells (OSC) produce secondary germ cells under the influence of OSC niche, including immune system-related cells and hormonal signaling.

How can female germline stem cells contribute to the physiological neo-oogenesis in mammals and why menopause occurs?

At the beginning of the last century, reproductive biologists have discussed whether in mammalian species the fetal oocytes persist or are replaced by neo-oogenesis during adulthood. Currently the prevailing view is that neo-oogenesis is functional in lower vertebrates but not in mammalian species. However, contrary to the evolutionary rules, this suggests that females of lower vertebrates have a better opportunity to provide healthy offspring compared to mammals with oocytes subjected to environmental threats for up to several decades.

In humans, zona pellucida glycoprotein-1 binds to spermatozoa and induces acrosomal exocytosis.

Background: It has been suggested that the zona pellucida (ZP) may mediate species-specific fertilization. In human the ZP is composed of four glycoproteins: ZP1, ZP2, ZP3 and ZP4. In the present study, the expression profile of ZP1 in human oocytes and ovaries, and its role during fertilization, is presented.

Immune physiology in tissue regeneration and aging, tumor growth, and regenerative medicine.

The immune system plays an important role in immunity (immune surveillance), but also in the regulation of tissue homeostasis (immune physiology). Lessons from the female reproductive tract indicate that immune system related cells, such as intraepithelial T cells and monocyte-derived cells (MDC) in stratified epithelium, interact amongst themselves and degenerate whereas epithelial cells proliferate and differentiate. In adult ovaries, MDC and T cells are present during oocyte renewal from ovarian stem cells.

Sex steroid-mediated reprogramming of vascular smooth muscle cells to stem cells and neurons: possible utilization of sex steroid combinations for regenerative treatment without utilization of in vitro developed stem cells.

Previous work from our laboratory demonstrated that sex steroid combinations, but not individual sex steroids alone, cause transdifferentiation of ovarian epithelial cells--ovarian surface epithelium (OSE) and follicular granulosa cells--into neural stem cells (NSC) and differentiating neurons. In the present study we have chosen primary culture of human vascular smooth muscle cells (SMC), a non-epithelial mesenchymal cells in order to test them as a control cell type regarding their morphology and expression of NSC and neuronal markers. Utilization of estradiol (E2), progesterone (PG) or testosterone (TS) alone did not induce the emergence of neurons from the vascular SMC.

Immune physiology and oogenesis in fetal and adult humans, ovarian infertility, and totipotency of adult ovarian stem cells.

It is still widely believed that while oocytes in invertebrates and lower vertebrates are periodically renewed throughout life, oocytes in humans and higher vertebrates are formed only during the fetal/perinatal period. However, this dogma is questioned, and clashes with Darwinian evolutionary theory. Studies of oogenesis and follicular renewal from ovarian stem cells (OSCs) in adult human ovaries, and of the role of third-party bone marrow-derived cells (monocyte-derived tissue macrophages and T lymphocytes) could help provide a better understanding of the causes of ovarian infertility, its prevention, and potential treatment.

Steroid-mediated differentiation of neural/neuronal cells from epithelial ovarian precursors in vitro.

We reported earlier that occasional neurons evolve in human cultures of pluripotent ovarian epithelial stem cells. In subsequent experiments, frequent transdifferentiation into neural stem cells (NSC) and differentiating neurons was observed in human ovarian epithelial stem cells and porcine granulosa cells after exposure to certain combinations of sex steroids. Testosterone (TS), progesterone (PG) or estradiol (E2) alone do not increase the emergence of neurons.

Differential transferrin expression in placentae from normal and abnormal pregnancies: a pilot study.

Background: The placenta is an important site for iron metabolism in humans. It transfers iron from the mother to the fetus. One of the major iron transport proteins is transferrin, which is a blood plasma protein crucial for iron uptake.

Study origin of germ cells and formation of new primary follicles in adult human and rat ovaries.

The central thesis regarding the human ovaries is that, although primordial germ cells in embryonal ovaries are of extraovarian origin, those generated during the fetal period and in postnatal life are derived from the ovarian surface epithelium (OSE) bipotent cells. With the assistance of immune system-related cells, secondary germ cells and primitive granulosa cells originate from OSE stem cells in the fetal and adult human gonads. Fetal primary follicles are formed during the second trimester of intrauterine life, prior to the end of immune adaptation, possibly to be recognized as self-structures and renewed later.

Production of monoclonal antibodies against recombinant human zona pellucida glycoproteins: utility in immunolocalization of respective zona proteins in ovarian follicles.

The zona pellucida (ZP) glycoproteins play an important role in oocyte development and gamete biology. To analyze their expression in follicles during various developmental stages, murine monoclonal antibodies (MAbs) were generated against the baculovirus-expressed recombinant human ZP2, ZP3 and ZP4. A panel of MAbs specific for the respective zona protein in ELISA and Western blot, and devoid of cross-reaction with other zona proteins was selected.

Mammalian neo-oogenesis and expression of meiosis-specific protein SCP3 in adult human and monkey ovaries.

The concept of neo-oogenesis and follicular renewal during adulthood in mammalian females, including humans, is a novel concept with major significance for ovarian physiology and mammalian reproductive biology. Previous observations from our laboratory demonstrated that mesenchymal cells in the tunica albuginea are bipotent progenitors for both granulosa and germ cells in adult human ovaries. In the present studies, we demonstrate that the antibodies against meiotic entry synaptonemal complex protein 3 (SCP3)--a marker or meiosis, showed reactivity with segments of tunica albuginea and ovarian surface epithelium, and in oocytes of some primordial follicles in functional human and monkey ovaries.

Oogenesis from human somatic stem cells and a role of immune adaptation in premature ovarian failure.

The central thesis is that, while embryonic oocytes originate from extra-ovarian sources, those generated during fetal period and in postnatal life are derived from the ovarian surface epithelium (OSE). With the assistance of immune system-related cells, primitive granulosa and germ cells appear to originate from OSE stem cells in the fetal and adult human gonads. Fetal primary follicles are formed during the second trimester of intrauterine life, prior to the end of immune adaptation, possibly in order to be recognized as self and renewed later.

Immune physiology of the mammalian ovary - a review.

The immune system, besides orchestrating the immune response, plays an important role in the regulation of tissue homeostasis. We refer to this later activity as 'immune physiology.' In human ovaries, immune system-related cells and molecules accompany corpus luteum development and regression and cancer progression.

Bone marrow derived cells and alternative pathways of oogenesis in adult rodents.

Oocyte generation in adult mouse ovaries by putative germ cells (PGCs) in bone marrow and peripheral blood has recently been proposed. It, however, remains unclear whether in laboratory rodents the PGCs reside in BM or the BM cells stimulate oogenesis from ovarian stem cells. We utilized immunoperoxidase staining to localize PGCs, oocytes, and BM derived cells in ovaries of adult (age 45-60 days) control and neonatally estrogenized rat females.

Cell commitment by asymmetric division and immune system involvement.

Asymmetric division is a fundamental means of generating cell diversity and may involve extrinsic or intrinsic factors. Here we review observations on symmetric and asymmetric expression of estrogen receptor alpha (ERA) and beta (ERB) during regeneration of trophoblast cells in human placenta and possibly other estrogen-responsive cell types. This is a type of differentiation from committed progenitor cells.

Ovarian germ cells.

Surface cells in adult ovaries represent germ line-competent embryonic stem cells. They are a novel type of totipotent progenitors for distinct cell types including female germ cells/oocytes, with the potential for use in the autologous treatment of ovarian infertility and stem cell therapy. Ovarian infertility and stem cell therapy are complex scientific, therapeutic, and socioeconomic issues, which are accompanied by legal restrictions in many developed countries.

Immune system involvement in the regulation of ovarian function and augmentation of cancer.

Increasing evidence indicates a role for the immune system and mesenchymal-epithelial interactions in the regulation of ovarian function. Cytokines produced by mesenchymal cells can stimulate development and regression of ovarian structures. We report here that mesenchymal cells releasing surface molecules among epithelial cells--namely vascular pericytes and monocyte-derived cells (MDC)--and intraepithelial T lymphocytes are associated with oogenesis and formation of new primary follicles in both fetal and adult human ovaries.

Potential new strategies for the treatment of ovarian infertility and degenerative diseases with autologous ovarian stem cells.

The 50-year-old and currently prevailing view that all oocytes in adult human ovaries persist from the fetal period of life is controversial as it clashes with Darwinian evolutionary theory. Studies of oogenesis and follicular renewal in adult human ovaries, and of the role of hormonal signals and third-party cells (tissue macrophages and T cells), could all be helpful in providing better understanding of the causes of ovarian infertility, its prevention and potential therapy. In addition, the authors recently reported differentiation of distinct cell types and the production of new eggs in cultures derived from premenopausal and postmenopausal human ovaries.

Can ovarian infertility be treated with bone marrow- or ovary-derived germ cells?

A year ago, reproductive biologists and general public were astonished with evidence reported by Johnson et al. in Nature 428:145 that mammalian ovaries possess persisting large germline stem cells, which allegedly enable follicular renewal in adult females. Recently, the same research group declared such view obscure, and reported that mammalian oocytes originate from putative germ cells in bone marrow and are distributed by peripheral blood to the ovaries (Cell 122:303).

Oogenesis in adult mammals, including humans: a review.

The origin of oocytes and primary follicles in ovaries of adult mammalian females has been a matter of dispute for over 100 yr. The prevailing belief that all oocytes in adult mammalian females must persist from the fetal period of life seems to be a uniquely retrogressive reproductive mechanism requiring humans to preserve their gametes from the fetal period for several decades. The utilization of modern techniques during last 10 yr clearly demonstrates that mammalian primordial germ cells originate from somatic cell precursors.