Conceptual development of endocrinology and stem cell research in parallel during approximately 100 years, from the beginning of last century to the onset of current century is briefly described, focusing on our own studies in the decades of 80s and 90s. It is justified that progression to a new subdiscipline of expanded endocrinology, as related to progenitor and stem cells should be promoted, considering not only “classical” hormones, but also various cytokines (growth factors, interleukins, chemokines, colony-stimulating factors), neurotransmitters, eicosanoids, many peptides and morphogens, etc. High complexity of these topics is outlined, suggesting the necessity of enhanced research efforts involving induced pluripotent stem cells in near future.

The term “stem cells” was used for the first time in 1909 by Russian histologist Alexander A. Maximow in the paper published in German, on the basis of his studies on hematopoiesis in bone marrow during his work in the Academy of Military Medicine in St. Petersburg (see discussion in [1]). At approximately the same time, in 1905 English physiologist Ernest Starling has used for the first time the term “hormone” [2], thus building chemical foundations for endocrinology, the science of internal secretion.

In our present article we are aiming at evaluation of parallel development of endocrinology and stem cell research during approximately one century, i.e., till 2005-2010. This is made in order to justify the necessity of a new subdiscipline that could describe in a broad sense the bioregulation of progenitor and stem cells by various substances including not only “classical” hormones, but also cytokines (interleukins, chemokines and growth factors), neurotransmitters, eicosanoids, various peptides, some morphogens, etc. [3].

The State of Stem Cell Research at the Onset of Third Millenium

Till the beginning of 21^st century it was already quite clear that stem and progenitor cells represent important components of healthy tissues and organs in adult human and animal bodies, as well as during pre- and postnatal development.

Although not strictly clarified, the difference was implied between stem and progenitor cells, considering stem cells as capable for auto-renewal, in contrast to progenitor cells [4]. Thus, stem cells are on the top of pyramidal cell cluster [5], generating progenitor cells by means of asymmetric divisions [6, 7]. Thereafter, progenitor cells continue to divide symmetrically, forming a cluster of transit-amplifying cells at the middle of pyramid and finally, less differentiated and more differentiated cells at the bottom of pyramid [8].

It is important to outline that in paradoxical mode stem cells divide quite rarely, as compared to progenitor (or transit-amplifying) cells. In various tumors this a principal reason for quite limited efficiency of chemotherapy that eliminates predominantly cancer progenitor but not stem cells [9, 10]. Another essential characteristics of stem cells are their extremely small size (~ 5 µm), as well as relatively large and euchromatin nucleus, and narrow rim of cytoplasm around it [11, 12]. In addition, important characteristics of stem and progenitor cells are high expression of telomerase [13, 14] and ABC transporters not allowing environmental toxins to accumulate inside these cells [5, 15]. Along the row of differentiation, the amount of cytoplasm gradually increases, together with appearance of proteins specific for differentiated cell types.

In several tissues the formation of polyploid cells substitutes for simple mitoses (because of the absence of cytokinesis), like in the liver (with 4n and higher ploidy nuclei) and in the heart (with binuclear cells). This allows to elevate the robustness of such tissues, but at the same time represents terminal differentiation, without possibility of return.

In many normal tissues of adult human and animal bodies there exist distinct locations for stem cells, according to data presented in table 1.

Table 1. Localization of stem cells in tissues and organs of adults.

What for pre- and postnatal development, here the situation appears to be more complicated. Great advances in our understanding of some of these aspects occurred after elaboration of cultures of embryonic stem cells (ESC) isolated from inner cell mass of pre-implantation blastocysts [16, 17]. It was confirmed that in some specific conditions ESC can be maintained in monolayer cultures almost indefinitely (with more than 300 population doublings) [18], although genomic instability can gradually appear, thus dictating the necessity of regular checking the risk of aneuploidy by means of karyotyping [19].

However, in suspension culture ESC rapidly aggregate, forming so called embryoid bodies, in which spontaneous differentiation is revealed [20]. One of the most notable events in this case is the appearance of spontaneously beating cells representing early cardiomyocytes [21]. In parallel, formation of blood cells and angiogenesis proceeds more or less in accordance with normal embryo-, organo- and histogenesis [15].

What for so called adult stem cells, from the very beginning principal focus was made on hematopoiesis in bone marrow, since, because of their small size and rare occurrence, stem cells are quite difficult to study and isolate from the majority of normal tissues of adult human and animal bodies.

Some Steps of Parallel Development in Endocrinology, Especially with our Participation

Although adrenaline (epinephrine) was discovered and synthesized close to the end of 19^th century, Ernest Starling applied the term “hormone” for the first time not to it, but to gastrointestinal secretin [2]. Thereafter several great events were gradual discovery, isolation and synthesis of many “classical” hormones including insulin, corticosteroids etc. along the 20^th century [22]. We entered this area in 1977 when Nobel prize was awarded partially for discovery and identification of hypothalamic hormones.

Fortunately, we had close contacts with experts in organic peptide chemistry, as well as primary adenohypophyseal cell cultures and homologous radioimmunoassays available in our hands. Thus, we were able during the decades of eighties and nineties of the last century to study the effects of thyrotropin-releasing hormone (TRH), somatostatin and many other peptides on prolactin (PRL) and growth hormone (GH) secretion, as well as on proliferation of cultured adenohypophyseal cells isolated from rats of different age groups: neonatal, prepubertal and adults [23, 24].

However, we began to discuss some aspects of stem and progenitor cells only as related to theoretical model of adenohypophyseal differone [25]. This model predicted the formation of clusters of pituitary cells during several divisions of progenitor cells with stepwise commitment of hormone production in the following sequence:

Stem cells à ACTH à TSH à LH / FSH à GH / PRL à PRL / GH,

where ACTH – adrenocorticotropic hormone, TSH – thyroid-stimulating hormone, LH – luteinizing hormone, FSH – follicle-stimulating hormone.

The discussion of this model was performed also in our recent publication [26]. Although in experimental studies we have observed higher sensitivity of DNA and total protein syntheses in neonatal rat pituitary cells to glucocorticoids (GC), melatonin and dopaminergic agonist bromocriptine, as compared to prepubertal and adult animals [27, 28], we don’t know yet if it can be explained by means of higher contents of stem or progenitor cells in younger animals. In pituitary cell cultures of adult rats, we observed the effects of TRH, somatostatin and dopaminergic agonist bromocriptine on proliferation of lactotrophs, i.e., prolactin-producing cells [29]. In theoretical model [25] we tried to explain this evidence by predominant localization of lactotrophs on external sides of pyramidal cluster of progenitor cells, thus partially escaping contact inhibition.

In our recent publication [26] we extended this discussion to adrenal cortex, suggesting the following sequence of commitments in steroid production during several divisions of progenitor cells:

Stem cells à GC / MC à ouabain à adrenal steroids,

where GC – glucocorticoids, MC – mineralocorticoids.

Moreover, we have suggested that the first 3 steps of both differones correspond to drastic changes in environments of early vertebrates:

• from salty oceans and seas to saltless water of rivers and lakes in fish (ACTH à GC / MC);
• from the water to coast of rivers and lakes in amphibia (TSH à T3 / T4 and ouabain);
• from coast to the land far from water supplies in reptiles and higher vertebrates, mammals and birds (FSH / LH à sex steroids in gonads and adrenals).

Of course, this theoretical construct can be considered only as preliminary one, and many other data should be gathered before its improvement or rejection, but one particular aspect attracts primary attention. In fact, in our studies during the last 30 years we have shown also the existence of transitions in postnatal development, as revealed by linearization in mono- and bilogarithmic coordinates of somatic growth plots in humans and rats. Thus, 3 evolutionary steps mentioned above may correspond to infantile, juvenile and pubertal transition respectively (in humans at the ages of 1-2, 6-8 and 12-14 years) [30].

Since according to our hypothesis of metamorphosis, the main transformation from development to aging occurs during juvenile transition [31], this may be explained by higher oxygen consumption during exit from aqueous environment to the land, being accompanied with necessary adjustment of heart beating frequency by means of ouabain.

Broadening Endocrinology as the Science of Bioregulation

Let’s discuss now in brief, what data allow us to suggest the possibility of expanded variant of endocrinology, as applied to progenitor and stem cells.

Table 2. Bioregulation of stem and progenitor cells, justifying expanded endocrinology.

Table 2 describes the situation up to the end of the first decade of current century. This summarized evidence largely confirms that stem and progenitor cells may be regulated by many cytokines including growth factors, interleukins and chemokines, colony-stimulating factors, some peptides like activin as well as steroid hormones, morphogens and many others. It means that our idea of broadening or expanded endocrinology [3] may be a good endeavor for near future, if to consider enormous possibilities opened by the techniques of induced pluripotent stem cells in culture (see discussion in [32]).

In conclusion, endocrinology of stem and progenitor cells can have very nice perspectives, especially if accompanied by parallel studies of transcription factors responsible for stemness and differentiation. In addition, our recent idea of gerontology as a science of ontogeny [33] (Goudochnikov, Prokhorov, 2023) can greatly favor the research of adult stem cells in the elderly, particularly as applied to oncology.

However, we ought to warn that stem cell research and expanded endocrinology may be quite complex. In fact, there exist > 200 different cell types in human body [34], a lot of growth factors [35] and > 2000 genes codifying transcription factors probably responsible for stemness and differentiation in human genome [36]. Future studies should also focus attention on the role of stem cell niches [37] (Scadden, 2006) and proteins responsible for cell adhesion, like integrins, fibronectin etc. [38].

Conflict of Interest

The author affirms that conflict of interest does not exist.

Funding

This work was performed according to personal initiative, without financial support from any source.

bFGF – basal fibroblast growth factor

BMP – bone morphogenetic protein

CNTF – ciliary neurotrophic factor

EGF – epidermal growth factor

ESC – embryonic stem cells

FGF – fibroblast growth factor

GM-CSF – granulocyte / macrophage colony-stimulating factor

HGF – hepatocyte growth factor

IGF-I – insulin-like growth factor type I

IL – interleukin

LIF – leukemia inhibitory factor

MAPC – multipotent adult progenitor cells

NO – nitric oxide

NT – neurotrophin

PDGF – platelet-derived growth factor

TGF – transforming growth factor

VEGF – vascular endothelial growth factor