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. Utilization of induced regeneration of tissues (regenerative medicine) is expected being more effective in sudden failures of younger individuals carrying intact SCN, as compared to established chronic disorders caused by SCN alteration. An essential component of SCN are monocyte-derived cells exhibiting tissue-specific "stop effect" (SE) preventing, for instance, an aging of neuronal cells. Its alteration causes that implantation of neuronal stem cells will also result in their differentiation toward aging cells. When we repair the SE by supply of circulating mononuclear cells from young healthy individuals, we may be able to provide novel regenerative treatments of age-induced neural diseases by sex steroid combinations. Questions regarding some age-induced body alterations are also addressed.

Antonin Bukovsky The Institute of Biotechnology Academy of Sciences of the Czech Republic Prague 14220 Czech Republic

Zobrazit více v PubMed

Bukovsky A. Immune maintenance of self in morphostasis of distinct tissues, tumour growth and regenerative medicine. Scand J Immunol. 2011;73:159–189. PubMed

Cameo P, Srisuparp S, Strakova Z, Fazleabas AT. Chorionic gonadotropin and uterine dialogue in the primate. Reprod Biol Endocrinol. 2004;2:50. PubMed PMC

Schumacher A, Costa SD, Zenclussen AC. Endocrine factors modulating immune responses in pregnancy. Front Immunol. 2014;5:196. PubMed PMC

Roobrouck VD, Vanuytsel K, Verfaillie CM. Concise review: culture mediated changes in fate and/or potency of stem cells. Stem Cells. 2011;29:583–589. PubMed

Rogers I. Transdifferentiation of endogenous cells: cell therapy without the cells. Cell Cycle. 2009;8:4027–4028. PubMed

Tesche LJ, Gerber DA. Tissue-derived stem and progenitor cells. Stem Cells Int. 2010;2010:824876. PubMed PMC

Choumerianou DM, Dimitriou H, Kalmanti M. Stem cells: promises versus limitations. Tissue Eng Part B Rev. 2008;14:53–60. PubMed

Li Y, Cang M, Lee AS, Zhang K, Liu D. Reprogramming of sheep fibroblasts into pluripotency under a drug-inducible expression of mouse-derived defined factors. PLoS One. 2011;6:e15947. PubMed PMC

Suhr ST, Chang EA, Rodriguez RM, Wang K, Ross PJ, Beyhan Z, Murthy S, Cibelli JB. Telomere dynamics in human cells reprogrammed to pluripotency. PLoS One. 2009;4:e8124. PubMed PMC

Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, Antosiewicz-Bourget J, O’Malley R, Castanon R, Klugman S, et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature. 2011;471:68–73. PubMed PMC

Bukovsky A. Novel methods of treating ovarian infertility in older and POF women, testicular infertility, and other human functional diseases. Reprod Biol Endocrinol. 2015;13:10. PubMed PMC

Caplan AI. Why are MSCs therapeutic? New data: new insight. J Pathol. 2009;217:318–324. PubMed PMC

Davidoff MS, Middendorff R, Müller D, Holstein AF. The neuroendocrine Leydig cells and their stem cell progenitors, the pericytes. Adv Anat Embryol Cell Biol. 2009;205:1–107. PubMed

Dohmann HF, Perin EC, Takiya CM, Silva GV, Silva SA, Sousa AL, Mesquita CT, Rossi MI, Pascarelli BM, Assis IM, et al. Transendocardial autologous bone marrow mononuclear cell injection in ischemic heart failure: postmortem anatomicopathologic and immunohistochemical findings. Circulation. 2005;112:521–526. PubMed

Augello A, Kurth TB, De Bari C. Mesenchymal stem cells: a perspective from in vitro cultures to in vivo migration and niches. Eur Cell Mater. 2010;20:121–133. PubMed

Bukovsky A. 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. Cell Cycle. 2009;8:4079–4084. PubMed

Sato M, Suzuki S, Senoo H. Hepatic stellate cells: unique characteristics in cell biology and phenotype. Cell Struct Funct. 2003;28:105–112. PubMed

Chow A, Lucas D, Hidalgo A, Méndez-Ferrer S, Hashimoto D, Scheiermann C, Battista M, Leboeuf M, Prophete C, van Rooijen N, et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J Exp Med. 2011;208:261–271. PubMed PMC

Wiley LA, Rupp GR, Steinle JJ. Sympathetic innervation regulates basement membrane thickening and pericyte number in rat retina. Invest Ophthalmol Vis Sci. 2005;46:744–748. PubMed

Wu DM, Kawamura H, Sakagami K, Kobayashi M, Puro DG. Cholinergic regulation of pericyte-containing retinal microvessels. Am J Physiol Heart Circ Physiol. 2003;284:H2083–H2090. PubMed

Gaytan F, Bellido C, Morales C, Reymundo C, Aguilar E, Van Rooijen N. Effects of macrophage depletion at different times after treatment with ethylene dimethane sulfonate (EDS) on the regeneration of Leydig cells in the adult rat. J Androl. 1994;15:558–564. PubMed

Seta N, Kuwana M. Derivation of multipotent progenitors from human circulating CD14+ monocytes. Exp Hematol. 2010;38:557–563. PubMed

Bukovsky A, Caudle MR. Sex steroid combinations in regenerative medicine for brain and heart diseases: The vascular stem cell niche and a clinical proposal. In Cell and Molecular Biology and Imaging of Stem Cells, Schatten H, ed. Hoboken: Wiley; 2014. pp. 193–210.

Hirokawa K, Utsuyama M, Kasai M, Kurashima C. Aging and immunity. Acta Pathol Jpn. 1992;42:537–548. PubMed

Bukovsky A, Caudle MR, Svetlikova M. Steroid-mediated differentiation of neural/neuronal cells from epithelial ovarian precursors in vitro. Cell Cycle. 2008;7:3577–3583. PubMed

Simpson ER. Aromatization of androgens in women: current concepts and findings. Fertil Steril. 2002;77 Suppl 4:S6–10. PubMed

Murakami H, Harada N, Sasano H. Aromatase in atherosclerotic lesions of human aorta. J Steroid Biochem Mol Biol. 2001;79:67–74. PubMed

Fuller SJ, Tan RS, Martins RN. Androgens in the etiology of Alzheimer’s disease in aging men and possible therapeutic interventions. J Alzheimers Dis. 2007;12:129–142. PubMed

Chamberlain G, Kitchin Y. Steroids in the assessment of prenatal development. Postgrad Med J. 1976;52:615–619. PubMed PMC

Wang JM, Liu L, Irwin RW, Chen S, Brinton RD. Regenerative potential of allopregnanolone. Brain Res Rev. 2008;57:398–409. PubMed

Thomas WE. Brain macrophages: on the role of pericytes and perivascular cells. Brain Res Brain Res Rev. 1999;31:42–57. PubMed

Shepro D, Morel NM. Pericyte physiology. FASEB J. 1993;7:1031–1038. PubMed

Doherty MJ, Ashton BA, Walsh S, Beresford JN, Grant ME, Canfield AE. Vascular pericytes express osteogenic potential in vitro and in vivo. J Bone Miner Res. 1998;13:828–838. PubMed

Bianco P, Riminucci M, Gronthos S, Robey PG. Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells. 2001;19:180–192. PubMed

Shi S, Gronthos S. Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp. J Bone Miner Res. 2003;18:696–704. PubMed

Farrington-Rock C, Crofts NJ, Doherty MJ, Ashton BA, Griffin-Jones C, Canfield AE. Chondrogenic and adipogenic potential of microvascular pericytes. Circulation. 2004;110:2226–2232. PubMed

da Silva Meirelles L, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci. 2006;119:2204–2213. PubMed

Mathé G. Immunity aging. I. The chronic perduration of the thymus acute involution at puberty? Or the participation of the lymphoid organs and cells in fatal physiologic decline? Biomed Pharmacother. 1997;51:49–57. PubMed

Hayden MR, Yang Y, Habibi J, Bagree SV, Sowers JR. Pericytopathy: oxidative stress and impaired cellular longevity in the pancreas and skeletal muscle in metabolic syndrome and type 2 diabetes. Oxid Med Cell Longev. 2010;3:290–303. PubMed PMC

Nishimura A. Are lectin positive spherical deposits detected in the molecular layer of the hippocampal formation related with neuronal apoptosis? J Med Invest. 2010;57:183–190. PubMed

Bukovsky A, Caudle MR, Carson RJ, Gaytán F, Huleihel M, Kruse A, Schatten H, Telleria CM. Immune physiology in tissue regeneration and aging, tumor growth, and regenerative medicine. Aging (Albany NY) 2009;1:157–181. PubMed PMC

Daadi MM. In vitro assays for neural stem cell differentiation. Methods Mol Biol. 2002;198:149–155. PubMed

Shihabuddin LS. Adult rodent spinal cord derived neural stem cells. Isolation and characterization. Methods Mol Biol. 2002;198:67–77. PubMed

O’Shea KS. Neural differentiation of embryonic stem cells. Methods Mol Biol. 2002;198:3–14. PubMed

Song S, Sanchez-Ramos J. Preparation of neural progenitors from bone marrow and umbilical cord blood. Methods Mol Biol. 2002;198:79–88. PubMed

Miki T, Strom SC. Amnion-derived pluripotent/multipotent stem cells. Stem Cell Rev. 2006;2:133–142. PubMed

Kuçi S, Kuçi Z, Schmid S, Seitz G, Müller I, Dufke A, Leimig T, Murti G, Jurecic R, Schumm M, et al. Efficient in vitro generation of adult multipotent cells from mobilized peripheral blood CD133+ cells. Cell Prolif. 2008;41:12–27. PubMed PMC

Scintu F, Reali C, Pillai R, Badiali M, Sanna MA, Argiolu F, Ristaldi MS, Sogos V. Differentiation of human bone marrow stem cells into cells with a neural phenotype: diverse effects of two specific treatments. BMC Neurosci. 2006;7:14. PubMed PMC

Hodges YK, Richer JK, Horwitz KB, Horwitz LD. Variant estrogen and progesterone receptor messages in human vascular smooth muscle. Circulation. 1999;99:2688–2693. PubMed

Hodges YK, Tung L, Yan XD, Graham JD, Horwitz KB, Horwitz LD. Estrogen receptors alpha and beta: prevalence of estrogen receptor beta mRNA in human vascular smooth muscle and transcriptional effects. Circulation. 2000;101:1792–1798. PubMed

Ma R, Wu S, Lin Q. Homologous up-regulation of androgen receptor expression by androgen in vascular smooth muscle cells. Horm Res. 2005;63:6–14. PubMed

Richards OC, Raines SM, Attie AD. The role of blood vessels, endothelial cells, and vascular pericytes in insulin secretion and peripheral insulin action. Endocr Rev. 2010;31:343–363. PubMed PMC

Westberg L, Eriksson E. Sex steroid-related candidate genes in psychiatric disorders. J Psychiatry Neurosci. 2008;33:319–330. PubMed PMC

Djebaili M, Guo Q, Pettus EH, Hoffman SW, Stein DG. The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats. J Neurotrauma. 2005;22:106–118. PubMed

Check JH, Levin E, Bollendorf A, Locuniak J. Miscarriage in the first trimester according to the presence or absence of the progesterone-induced blocking factor at three to five weeks from conception in progesterone supplemented women. Clin Exp Obstet Gynecol. 2005;32:13–14. PubMed

Borna S, Sahabi N. Progesterone for maintenance tocolytic therapy after threatened preterm labour: a randomised controlled trial. Aust N Z J Obstet Gynaecol. 2008;48:58–63. PubMed

Gray PB, Singh AB, Woodhouse LJ, Storer TW, Casaburi R, Dzekov J, Dzekov C, Sinha-Hikim I, Bhasin S. Dose-dependent effects of testosterone on sexual function, mood, and visuospatial cognition in older men. J Clin Endocrinol Metab. 2005;90:3838–3846. PubMed

Coviello AD, Kaplan B, Lakshman KM, Chen T, Singh AB, Bhasin S. Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. J Clin Endocrinol Metab. 2008;93:914–919. PubMed PMC

Schram JH, Boerrigter PJ, The TY. Influence of two hormone replacement therapy regimens, oral oestradiol valerate and cyproterone acetate versus transdermal oestradiol and oral dydrogesterone, on lipid metabolism. Maturitas. 1995;22:121–130. PubMed

Bukovsky A, Caudle MR, Keenan JA, Upadhyaya NB, Van Meter SE, Wimalasena J, Elder RF. Association of mesenchymal cells and immunoglobulins with differentiating epithelial cells. BMC Dev Biol. 2001;1:11. PubMed PMC

Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature. 2005;433:760–764. PubMed

Bukovský A, Michael SD, Presl J. Cell-mediated and neural control of morphostasis. Med Hypotheses. 1991;36:261–268. PubMed

Gubriĭ IB, Reznikov AG, Demchenko VN, Butenko GM. [Cessation of ovarian cycles in a young mouse while in parabiosis with an older one] Biull Eksp Biol Med. 1987;103:205–208. PubMed

Cuk M, Radosević-Stasić B, Milin C, Kirigin M, Rukavina D. Lymphoid system as a regulator of morphostasis and hormonal modulation of these functions. Ann N Y Acad Sci. 1987;496:104–107. PubMed

Williams AF, Barclay AN. The immunoglobulin superfamily--domains for cell surface recognition. Annu Rev Immunol. 1988;6:381–405. PubMed

Boels D, Landreau A, Bruneau C, Garnier R, Pulce C, Labadie M, de Haro L, Harry P. Shiitake dermatitis recorded by French Poison Control Centers - new case series with clinical observations. Clin Toxicol (Phila) 2014;52:625–628. PubMed

Bukovsky A. Novel Immunological Aspects for the Treatment of Age-induced Ovarian and Testicular Infertility, Other Functional Diseases, and Early and Advanced Cancer Immunotherapy. In Human Reproduction: Updates and New Horizons, Schatten H, editor. Hoboken: Wiley; 2015. p. In press.

Bukovsky A. The role of resident monocytes and vascular pericytes in the stem cell niche and regenerative medicine. Stem Cell Stud. 2011;1:126–147. Available from: http://www.pagepress.org/journals/index.php/scs/article/view/scs.2011.e20/pdf.

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