U.K. Study shows earlier Fetus Heartbeat
(featured image: Fetus at 4 weeks)
After a female ovulates and has unblocked intercourse in which the sperm penetrates; then the egg can become fertilized within a day and as it divides into multiple cells it travels down the Fallopian tube enters the uterus and embeds into the lining. The egg becomes a blastocyst and already begins to affect the mother or host – telling her body to stop releasing eggs. And according to Microbiology, before a women even knows she is pregnant, after the one in hundreds of million sperm penetrates a mature egg and creates a single set of 46 chromosomes conception takes place and a Zygote (cell organism) is formed; it is the basis for a new human being.
After a couple of days the Zygote becomes a Morula (solid ball of cells) traveling through the fallopian tube. As early as a week after conception, the Morula has become a Blastocyst (from the Greek ‘sprout’ ‘capsule’) and embeds into the uterine lining, beginning the embryonic stage. The embryonic time is about 56 days or 8 weeks from fertilization. An Embryo is defined scientifically as ‘an unborn offspring in the process of development;’ and as an ‘unborn child.’ According to microbiology as a Zygote is formed: ‘life begins at conception. ’
According to standard biology teaching and most websites (babycentre.com; whattoexpect.com; etc.) it is not until around the end of the first month or ‘5 Weeks Pregnant’ that they say, ‘your baby’s tiny heart is already dividing into chambers and will soon begin pumping blood’ or ‘the heartbeat may be visible’ as ‘your baby will have a functioning heart.’ http://www.ehd.org states “about 3 weeks, one day after fertilization, when the heart first begins to beat…”
http://www.Webmd.com does ‘at 4 Weeks’ state ‘the heart and blood vessels continue to develop.’ Nevertheless, an AOL News article, October 11, 2016, entitled ‘A fetus’ heartbeat starts days earlier than we thought it did,’ reports: “The first organ to form inside a human fetus is the heart. And new research says that heart might start beating earlier than we previously thought it did. A team of U.K. scientists just published a paper pinpointing at what stage of development a heartbeat begins… The study records the first heartbeat at 7.5 days after conception for lab mice — the Daily Mail says that’s about 16 days for humans. It was previously thought that the human heart started beating about three to four weeks after conception.
http://www.elifesciences.org article published October 11, 2016, called Calcium handling precedes cardiac differentiation to initiate the first heartbeat cites a joint Study by scientists from the University of Oxford, University College London and Medical School, and Wellcome Trust, United Kingdom lead by Doctors Tyser, Miranda, Chen, Davidson, Srinivas and Riley.
The Abstract states: “The mammalian heartbeat is thought to begin just prior to the linear heart tube stage of development. How the initial contractions are established and the downstream consequences of the earliest contractile function on cardiac differentiation and morphogenesis have not been described. Using high-resolution live imaging of mouse embryos, we observed randomly distributed spontaneous asynchronous Ca2+-oscillations (SACOs) in the forming cardiac crescent (stage E7.75) prior to overt beating…”
Then the article reports, eLife digest: “The heart is the first organ to form and to begin working in an embryo during pregnancy. It must begin pumping early to supply oxygen and nutrients to the developing embryo. Coordinated contractions of specialised muscle cells in the heart, called cardiomyocytes, generate the force needed to pump blood. The flow of calcium ions into and out of the cardiomyocytes triggers these heartbeats. In addition to triggering heart contractions, calcium ions also act as a messenger that drives changes in which genes are active in the cardiomyocytes and how these cells behave.
Scientists commonly think of the first heartbeat as occurring after a tube-like structure forms in the embryo that will eventually develop into the heart. However, it is not yet clear how the first heartbeat starts or how the initial heartbeats affect further heart development.
Tyser, Miranda et al. now show that the first heartbeat actually occurs much earlier in embryonic development than widely appreciated. In the experiments, videos of live mouse embryos showed that prior to the first heartbeat the flow of calcium ions between different cardiomyocytes is not synchronised. However, as the heart grows these calcium flows become coordinated leading to the first heartbeat. The heartbeats also become faster as the heart grows. Using drugs to block the movement of calcium ions, Tyser, Miranda et al. also show that a protein called NCX1 is required to trigger the calcium flows prior to the first heartbeat. Moreover, the experiments revealed that these early heartbeats help drive the growth of cardiomyocytes and shape the developing heart.
Together, the experiments show that the first heartbeats are essential for normal heart development. Future studies are needed to determine what controls the speed of the first heartbeats, and what organises the calcium flows that trigger the first heartbeat. Such studies may help scientists better understand birth defects of the heart, and may suggest strategies to rebuild hearts that have been damaged by a heart attack or other injury.”
The Article continues with the ‘Main Text’ ‘Introduction’ in part stating:
“The heart is the first organ to form and function during mammalian embryonic development. In the mouse, mesoderm originating from the primitive streak forms a bilateral pool of progenitor cells that at E7.5 give rise to the cardiac crescent (CC). The CC subsequently expands and migrates to the midline whereupon, between E8.25 and E8.5, the two sides of the CC fuse and form the linear heart tube (LHT) (reviewed in Buckingham et al., 2005). The first cardiac contractions have been described during the transition from CC to LHT. Studies of heart development in model organisms have historically focused on the origin and spatial-temporal allocation of cardiac progenitors and cardiovascular lineage determination…’
“Given the forming heart contracts from an early stage, this raises the important question of when and how contractile activity of cardiomyocytes is first initiated during development and to what extent this influences the progression of differentiation and subsequent cardiac morphogenesis. This is especially important as the forces exerted by cardiac contractions have been shown in several models to be required for proper heart development (Granados-Riveron and Brook, 2012), and to modulate gene expression (Miyasaka et al., 2011) at later developmental stages…’
“Whilst these studies characterised SR function at ~E8.5–9, they did not investigate how Ca2+ transients are regulated at the earliest stages of cardiac crescent development when contraction is initiated, and relied on experiments performed using isolated cells cultured for between 12 to 70 hr (Sasse et al., 2007; Rapila et al., 2008). Thus there is a lack of cellular resolution in vivo and no current mechanistic insight into the onset of Ca2+ handling and its impact on differentiation and cardiogenesis.
We report here, for the first time, high-resolution live imaging of Ca2+ transients during the earliest manifestation of murine heart development well before any indication of spontaneous cardiac contractions. We employed the use of multiple pharmacological inhibitors to address the contribution of the NCX1 and LTCC Ca2+ channels during this process and reveal an essential early role for NCX1-dependent Ca2+ handling on downstream cardiac differentiation and morphogenesis…”
Under ‘Results’ their Study reports:
“It is commonly stated that initiation of contraction begins with the formation of the LHT (Bruneau, 2008), and whilst cardiac contractions have been reported just prior to the ‘linear heart tube’ stage (Navaratnam et al., 1986; Nishii and Shibata, 2006; Linask et al., 2001; Kumai et al., 2000; Porter and Rivkees, 2001), a precise study on the initiation of cardiac function has not been conducted. A difficulty with these reports is the use of ‘embryonic day’ or ‘somite number’ to stage the developing heart. Somite number is variable in its correlation to the overall embryonic stage (Kaufman and Navaratnam, 1981), can depend on genetic background (Méry et al., 2005; Porter and Rivkees, 2001) and importantly, is not a sufficiently fine-grained proxy for the developmental stages of the heart. This can lead to ambiguities, as a ‘3-somite’ embryo may range from the cardiac crescent to early LHT stages. We, therefore, created a staging system specific to the early heart, from early crescent to LHT (Supplementary file 1a), similar to studies at later stages when a more precise morphological characterization is necessary (Biben and Harvey, 1997). On this basis, we defined four stages (0, 1, 2 and 3) of cardiac crescent development prior to the LHT stage, based on clear morphological differences. Stage 0 hearts represented the first discernible crescent structure situated beneath the developing head folds, being the widest (360–390 µm along the medio-lateral axis) and thinnest (70–80 µm along the rostro-caudal axis) of the crescent stages (Supplementary file 1a). Whilst stage 1 was morphologically similar to stage 0, the cardiac crescent had become narrower (300–370 µm) and thicker (75–95 µm). By stage 2, folding of the cardiac crescent is evident based on the formation of a trough at the embryonic midline and two lobes on either side. As the embryo transitions to stage 3 this trough becomes less obvious with a rostral-caudal elongation of the heart as the LHT begins to form. Transition from stage 3 to the LHT was defined by the complete fusion of the two lobes and loss of the central trough (Figure 1; Supplementary file 1a)…”
The Study and Article goes on with much technical biology and video images and detailed science. For example they stated, “We performed a similar analysis on EB derived cardiomyocytes. Slc8a1 expression increased significantly in EBs prior to Cacna1c (day 2 versus day 4; Figure 3B,C) and to a much greater extent with the onset of beating (110 fold versus 38 fold; Figure 3B,C), suggesting NCX1 might play a more immediate role in the onset of beating.” And in their ‘Discussion’ section they add in part: “Previous studies have attempted to investigate how cardiac function develops within the early embryo. Whilst these studies are informative they rely on the dissociation and culture of embryonic cardiomyocytes to facilitate physiological measurements resulting in the loss of critical spatial and temporal information regarding Ca2+-handling and downstream changes in gene expression and morphology. Using a staging method based on morphological landmarks (stages 0–3), we characterized in detail the in vivo progression of physiological activity during early heart development. The stage series defined correlates with gradual expression of several cardiac related genes and sarcomere assembly. We observed spontaneous asynchronous Ca2+ oscillations (SACOs) at stage 0 in the developing cardiac mesoderm, before any detectable cardiac contractions. These transients appeared sporadically in individual cells within the forming cardiac crescent and did not appear to be synchronized. At stage 1, periodic Ca2+ transients began to be propagated laterally through the cardiac crescent, and traversed the midline of the crescent where there were no visible contractions…”
“THE PACEMAKER CELL”
“The observation of spontaneous asynchronous calcium oscillations (SACOs) within the forming cardiac crescent was a surprising finding that, to the best of our knowledge, has not previously been reported in any type of excitable cell. The specific role of SACOs is currently unknown and we hypothesise that they are required in cells that need to optimally activate Ca2+-dependent signalling (via the CAMKII pathway) in order to up-regulate genes necessary for further differentiation and morphogenesis. This would explain why SACOs are present much earlier than complete sarcomere assembly. An alternative hypothesis is that SACOs are a by-product of cells that are already committed to specific cardiac lineages and, therefore, arise with the expression of specific channels required for future function. This could explain the variation in duration and frequencies of SACOs observed within the same embryo. At this point, quite how SACOs become synchronised transients is unknown. We speculate that release of a Ca2+-dependent signal from a ‘pacemaker’ cell may entrain neighbours to have synchronised transient periodicity. To this end we observed highly variable Ca2+ periodicity but also regions containing cells of similar periodicity (Video 2). Since blockade of NCX1 prior to the formation of the cardiac crescent, and chronic treatment in ESCs, leads to impaired cardiac differentiation it is also possible that SACOs may be present in mesoderm cells earlier than reported here, which we were not able to image due to the limitations of the current experimental set-up.”