Why are hematopoietic stem cells so 'sexy'? on a search for developmental explanation.

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Abstract

Evidence has accumulated that normal human and murine hematopoietic stem cells express several functional pituitary and gonadal sex hormones, and that, in fact, some sex hormones, such as androgens, have been employed for many years to stimulate hematopoiesis in patients with bone marrow aplasia. Interestingly, sex hormone receptors are also expressed by leukemic cell lines and blasts. In this review, I will discuss the emerging question of why hematopoietic cells express these receptors. A tempting hypothetical explanation for this phenomenon is that hematopoietic stem cells are related to subpopulation of migrating primordial germ cells. To support of this notion, the anatomical sites of origin of primitive and definitive hematopoiesis during embryonic development are tightly connected with the migratory route of primordial germ cells: from the proximal epiblast to the extraembryonic endoderm at the bottom of the yolk sac and then back to the embryo proper via the primitive streak to the aorta-gonado-mesonephros (AGM) region on the way to the genital ridges. The migration of these cells overlaps with the emergence of primitive hematopoiesis in the blood islands at the bottom of the yolk sac, and definitive hematopoiesis that occurs in hemogenic endothelium in the embryonic dorsal aorta in AGM region.Leukemia advance online publication, 26 May 2017; doi:10.1038/leu.2017.148.

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Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells.

Anthony Boitano, Jian Wang, Russell D. Romeo … (2010)

Although practiced clinically for more than 40 years, the use of hematopoietic stem cell (HSC) transplants remains limited by the ability to expand these cells ex vivo. An unbiased screen with primary human HSCs identified a purine derivative, StemRegenin 1 (SR1), that promotes the ex vivo expansion of CD34+ cells. Culture of HSCs with SR1 led to a 50-fold increase in cells expressing CD34 and a 17-fold increase in cells that retain the ability to engraft immunodeficient mice. Mechanistic studies show that SR1 acts by antagonizing the aryl hydrocarbon receptor (AHR). The identification of SR1 and AHR modulation as a means to induce ex vivo HSC expansion should facilitate the clinical use of HSC therapy.

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Blimp1 is a critical determinant of the germ cell lineage in mice.

Yasuhide Ohinata, Bernhard Payer, Dónal O'Carroll … (2005)

Germ cell fate in mice is induced in pluripotent epiblast cells in response to signals from extraembryonic tissues. The specification of approximately 40 founder primordial germ cells and their segregation from somatic neighbours are important events in early development. We have proposed that a critical event during this specification includes repression of a somatic programme that is adopted by neighbouring cells. Here we show that Blimp1 (also known as Prdm1), a known transcriptional repressor, has a critical role in the foundation of the mouse germ cell lineage, as its disruption causes a block early in the process of primordial germ cell formation. Blimp1-deficient mutant embryos form a tight cluster of about 20 primordial germ cell-like cells, which fail to show the characteristic migration, proliferation and consistent repression of homeobox genes that normally accompany specification of primordial germ cells. Furthermore, our genetic lineage-tracing experiments indicate that the Blimp1-positive cells originating from the proximal posterior epiblast cells are indeed the lineage-restricted primordial germ cell precursors.

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Estrogen increases haematopoietic stem cell self-renewal in females and during pregnancy

Daisuke Nakada, Hideyuki Oguro, Boaz Levi … (2014)

SUMMARY Sexually dimorphic mammalian tissues, including sexual organs and the brain, contain stem cells that are directly or indirectly regulated by sex hormones 1-6 . An important question is whether stem cells also exhibit sex differences in physiological function and hormonal regulation in tissues that do not exhibit sex-specific morphological differences. The terminal differentiation and function of some haematopoietic cells are regulated by sex hormones 7-10 but haematopoietic stem cell (HSC) function is thought to be similar in both sexes. Here we show that mouse HSCs exhibit sex differences in cell cycle regulation by estrogen. HSCs in females divide significantly more frequently than in males. This difference depended on the ovaries but not the testes. Administration of estradiol, a hormone produced mainly in the ovaries, increased HSC cell division in males and females. Estrogen levels increased during pregnancy, increasing HSC division, HSC frequency, cellularity, and erythropoiesis in the spleen. HSCs expressed high levels of estrogen receptor α (ERα). Conditional deletion of ERα from HSCs reduced HSC division in female, but not male, mice and attenuated the increases in HSC division, HSC frequency, and erythropoiesis during pregnancy. Estrogen/ERα signaling promotes HSC self-renewal, expanding splenic HSCs and erythropoiesis during pregnancy.