Circadian Release of HSCs

Last month, Méndez-Ferrer S et al. published an article on Nature, exploring the circadian pattern of haematopoietic stem cell release.

First, by applying continuous light, continuous dark, and jet-lag environmental cue, the authors showed a regularly circadian pattern of haematopoietic stem cells release, through analyzing colony-forming units in culture (CFU-C) and LSK cells (lineage-negative Sca-1 + c-Kit +) from blood. The peak reaches at 5 hour of Zeitgeber time, and nadir lies 17 hour of Zeitgeber time (5 hours after the start point of darkness). This rhythmic oscillation is maintained in total darkness, gets a shift during jet lag, and becomes arrhythmic in continuous light.

Stemming from that Cxcl12 (SDF-1, stromal cell-derived factor-1) is the only known chmokine capable of directed migration of HSCs, they further investigated the impact on Cxcl2 of bone marrow cells in both protein and mRNA expression by manupilating the circadian cycle. The results obeyed the circadian oscillations. But Cxcl12 flatuations mirrored that of HSCs both in protein and mRNA level, which is consistent with current proposed model.

In advance, the authors digged into the relationship between sympathetic nervous system (SNS) and the circadian pattern of HSCs release, plus Cxcl12 expression. Employing the neurochemical sympathectomy approach with 6-hydroxydopamine (6OHDA), the circadian pattern of HSCs by CFU-Cs was abolished. The authors then did surgical sympathectomy by unilateral microsection of both sciatic and femoral nerves. Compared with the sham-operated side, the circadian pattern of Cxcl2 is detroyed in the denervated side.
Moreover, the authors discerned that this Cxcl12 circadian effect is mediated by β3 adrenergic receptors pharmacologically, with series of in vitro bone marrow stromal cells (MS-5) treated by a variety of adrenergic agonists or antagonists.

This is a very decent paper dissecting the circadian oscillation and release of HSC and Cxcl12 expression. However, this raise a question mark in my mind. First, is adrenaline secreted circadianly? To my knowledge, adrenaline from ANS (autonomic nerve system), or any catecholamine, is not secreted in a circadian pattern. They are usually episodic, elevated when needed such as coping stress. What I can think of most, is that ACTH (adrenocorticotropic hormone) is circadian, driving corticosteroid and minerosteroid to be circadian, and may partly act on medulla and contribute adrenaline from adrenal glands to total adrenaline.

Second, neither sciatic nor femoral nerves is pure sympathetic nerve. Denervation of sciatic and femoral nerves will cause far more downstream physiological effects than just sympathectomy. Denervation itself and subsequent biological changes would be a big topic to be explored. I would challenge this model as an evidence to illustrate adrenaline's role on Cxcl12 expression.

Despite the above-mentioned questioning, it is very important to know that release of HSCs is circadian. I believe that such the finding will benefit medicine in application for either chemotherapy or transplantation.

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Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Medicine, Biomedical Science, Biological Science, Medical Science, Biological Science, Medicine-Haematology, Medicine-Oncology, Medicine-Transplantation, Medicine-Immunology, Medicine-Molecular Biology, Medicine-Molecular Medicine, Medicine-Cell Biology, Medicine-Developmental Biology, Circadian cycle, HSC, HSCs, Haematopoietic stem cell, Jet-lag, Environmental cue, LSK cells, lin - Sca-1 + c-Kit +, Zeitgeber, CXCL12, Cxcl12, chemokines, Cytokines, bone marrow, SNS, sympathetic nerve system, sympathectomy, 6OHDA, 6-hydroxydopamine, sciatic nerve, femoral nerve, tibia denervation, adrenergic receptor, Medicine-Pharmacology, bone marrow stromal cells, MS-5, ANS, autonomic nerve system, catecholamine, ACTH, adrenocorticotropin, corticosteroid, minerosteroid, medulla, adrenal gland, Medicine-Endocrinology, Denervation, Medicine-Neurology, chemotherapy, Medicine-Cancer Biology, adrenaline

Update of Free Museum Admissions Provided by Bank of America

As my last post in regard to Bank of America's promotion, here comes the details.

The unexpected change compared to that of last year is, in contrast to one cardholder can get two tickets at the booth last year, this time the free admission is limited to cardholder only. In other words, friends, or children who do not have Bank of America card will need to pay. Thus the event this year, although still a feast to reward their old customers, is more a campaign to drive more people to create financial relationships with them.

As to the participating museums, it has dropped from 95 to 70. Some big famous museums are no longer on the list, but the good side is they spread out to more cities and more states.

I should say, despite the down sides, this is still a decent deal - the first weekend for every month, and last for one full year! So, get it ready with your Bank of America ATM or Debit or Credit Card (disclaimer: Wilfred Wu Wonderland is not affiliated with Bank of America, her holding company[ies], or her subsidiary[ies]), and remember to bring your photo ID. Line up and get a free ticket to enjoy a mindful of arts or science, with no extra charges.

Their official disclosure webpage: http://www.bankofamerica.com/museums

Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]
Tags: Free!, Museum, Admission, Admissions, Museum Admission, Museum Admissions, Free Museum Admission, Free Museum Admissions, Bank of America, Bank of America customers, Cardholder, ATM card, Debit card, Credit card

Is Warburg Effect Determined by Embryonic Isoform of Pyruvate Kinase?

It has been more than 75 years since Dr. Otto Warburg disclosed the aerobic glycolysis in tumor cells around 1930. This metabolic phenomenon in tumors, seperating it from Kreb's cycle and anerobic fermentation, features high rates of glucose uptake, but low rates of oxidative phosphorylation, with production of lactic acid even in the presense of oxygen. The principles of aerobic glycolysis has been applied to fancy, popular approach to detect cancer recurrence sucha as PET (Positron Emission Tomography) in nuclear medicine contemporarily. Yet there are more to be explored, and potentially there may be more to be exploited in cancer treatment or prevention.

Christofk HR et al. published a paper on Nature last month which likns Warburg's observation to embryonic isoform of pyruvate kinase, M2. It has been known that cancer cells express embryonic M2 isoform of pyruvate kinase exclusively.

The authros first verified this exclusive expression of M2 isoform in cancer tissue by immunoblotting and immunohistochemistry. Then, using short hairpin RNA (shRNA) knockdown in H1299 cells (a human lung cancer cell line), plus rescue by mouse PKM1 (pyruvate kinase M1 isoform) and PKM2 (pyruvate kinase M2 isoform), they revealed that M2 isoform rescues more, in terms of glycolytic rate and replication. Moreover, M2 cells are mroe resistant to hypoxic circumstances, and mitochondrial ATP synthase inhibitor, oligomycin. Even more, ocygen consumption is lower in cells bearing M2 compensation, and lactate production is significantly higer. These findings succesfully connect M2 isoform of pyruvate kinase to Walburg's aerobic glycolysis as a determinant to escape tricarboxylic acid cycle and to enter the pathway for lactate production.

In the meantime, the authors also employed xenograft study on nude mouse by injecting H1299 tumor cells with M1 or M2 expression. This in vivo model resulted in bigger tumor, and more probablity to form tumors by lung cancer cell line bearing mouse M2 isoform vector.

I should say this is not intuitive, or even a violation of my current knowledge of biochemistry and glucose metabolism. Shouldn't the determining factors for entering citric cycle or lactic acid production lie after pyruvate? Are the end product of pyruvate by different isoform of pyruvate kinase different? Or, does pyruvate kinase act after pyruvate formation, and drive them into distinct destiny according to specific isoform? Or, doses the conformation of pyruvate kinase give it the ability to intervene the downstream reaction? (More spatial and temporal questions to be asked)

If we put aside these questions to clarify and make things consistent and focus on the applications, we may also ask how do cells switch from the adult M1 isoform of pyruvate kinase back to embronic M2 isoform? It is known that M2 isoform is a splice variant of M1, and how do we control than?

Although my questions may sound absurd, but I do take the authors' findings very seriously as an important breakthrough in cancer biology with great potential to further study, cancer treatment, and prevention.



Wilfred Wu Wonderland [ Portal | 1996 edition | 2001 edition | 2006 Blog ]

Tags: Medicine, Medicine-Oncology, Medicine-Cancer Biology, Medicine-Biochemistry, Medicine-Nuclear Medicine, Medicine-Biomedical Science, Medicine-Biological Science, Medicine-Bioscience, Dr. Otto Warburg, glycolysis, Aerobic glycolysis, citric cycle, citrate cycle, Kerb's cycle, TCA cycle, Tricarboxylic acid cycle, Anaerobic fermentation, Anaerobic glycolysis, Lactate cycle, Pyruvate, Pyruvate Kinase, Glucose metabolism, Cancer Cell metabolism, Pyruvate Kinase, M2 isoform, Embryonic isoform, Medicine-Developmental Biology, M1 isoform, Adult isoform, Immunoblotting, Immunohistochemistry, shRNA knockdown, hypoxia, mitochondrial ATP synthase, nude mouse, xenograft study, conformation change