Circadian Variations in Clock Gene Expression of Human Bone Marrow CD34+ Cells

Abstract

Time-dependent variations in clock gene expression have recently been observed in mouse hematopoietic cells, but the activity of these genes in human bone marrow (BM) has so far not been investigated. Since such data can be of considerable clinical interest for monitoring the dynamics in stem/progenitor cells, the authors have studied mRNA expression of the clock genes hPer1 , hPer2, hCry1, hCry2, hBmal1, hRev-erb alpha, and hClock in human hematopoietic CD34-positive (CD34( +)) cells. CD34(+) cells were isolated from the BM samples obtained from 10 healthy men at 6 times over 24 h. In addition, clock gene mRNA expression was analyzed in the whole BM in 3 subjects. Rhythms in serum cortisol, growth hormone, testosterone, and leukocyte counts documented that subjects exhibited standardized circadian patterns. All 7 clock genes were expressed both in CD34(+) cells and the whole BM, with some differences in magnitude between the 2 cell populations. A clear circadian rhythm was shown for hPer1, hPer2, and hCry2 expression in CD34(+) cells and for hPer1 in the whole BM, with maxima from early morning to midday. Similar to mouse hematopoietic cells, h Bmal1 was not oscillating rhythmically. The study demonstrates that clock gene expression in human BM stem/progenitor cells may be developmentally regulated, with strong or weaker circadian profiles as compared to those reported in other mature tissues.

The peripheral nervous system supports blood cell homing and survival in theDrosophilalarva

“…This, together with the direct or indirect trophic dependence of hemocytes on the PNS, clearly distinguishes our findings from the previously reported role of hemocytes in dendrite and axon pruning, which typically is initiated at the onset of metamorphosis (Watts et al, 2003;Han et al, 2011). A functional connection of the PNS with the hematopoietic system might be of fundamental importance across species: in vertebrates, PNS activity governs regulation of HSC egress from the bone marrow and proliferation (Mauer, 1965;Katayama et al, 2006;Tsinkalovsky et al, 2007;Lucas et al, 2008;Mendez-Ferrer et al, 2008;MendezFerrer et al, 2010), and immune responses in lymphocytes and myeloid cells (Mignini et al, 2003;Shepherd et al, 2005). Indeed, all hematopoietic tissues, such as bone marrow, thymus, spleen and lymph nodes, are highly innervated by the sympathetic and, in some cases in addition, the sensory nervous system (Shepherd et al, 2005;Nance and Sanders, 2007).…”

Clock Genes Display Rhythmic Expression in Human Hearts

“…In humans, clock genes have been described only in a few tissues, like oral mucosa (Bjarnason et al, 1999), peripheral mononucleocytes Desan et al, 2000;James et al, 2007;Takimoto et al, 2005), bone marrow cells (Tsinkalovsky et al, 2007), skeletal muscle (Zambon et al, 2003), adipocytes (Gomez-Abellan et al, 2008), and cancer specimens (Chen et al, 2005;Chen-Goodspeed & Lee, 2007;Gery et al, 2006;Krugluger et al, 2007;Sahar & Sassone-Corsi, 2007;Winter et al, 2007). They have yet to be analyzed in human cardiovascular cells, although the exact reasons for the accumulation of cardiac incidents in the morning are still not entirely clear (Kawakami et al, 2008;Willich et al, 1991).…”

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

“…This phenomenon has been demonstrated in thymocytes (Ranges et al, 1988;Hernán-dez-Caselles and Stutman, 1993), hepatocytes (Bour et al, 1996;Diehl and Rai, 1996), hematopoiesis (Clark and Chaudhri, 1988;Rebel et al, 1999) and, of plausible relevance to data from AD brains (Sheng et al, 2012), impaired mitochondria biogenesis (Valerio et al, 2006). The relevance of TNF-induced insulin resistance to the pathogenesis of the widespread degenerative change that characterizes chronic inflammatory diseases can be gleaned from the literature on endothelial cell progenitors (Cubbon et al, 2009;Abbas et al, 2011;Desouza et al, 2011) and thus nephropathy; muscle progenitors (Pajak et al, 2008) and thus cachexia; fibroblast progenitors (Frankel et al, 2006;Goren et al, 2006;Siqueira et al, 2010) and thus poor wound healing; cartilage progenitors Kayal et al, 2009) and thus poor fracture repair; and erythroblasts (Tsinkalovsky et al, 2007) and thus the anemia of chronic disease. Whether the recorded protective effect of sex hormones in some of these circumstances is an independent property parallel to their ability to reduce production of TNF (He et al, 2004;Kipp et al, 2007) is a yet to be tested.…”