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Pregnancy Timeline by SemestersDevelopmental TimelineFertilizationFirst TrimesterSecond TrimesterThird TrimesterFirst Thin Layer of Skin AppearsEnd of Embryonic PeriodEnd of Embryonic PeriodFemale Reproductive SystemBeginning Cerebral HemispheresA Four Chambered HeartFirst Detectable Brain WavesThe Appearance of SomitesBasic Brain Structure in PlaceHeartbeat can be detectedHeartbeat can be detectedFinger and toe prints appearFinger and toe prints appearFetal sexual organs visibleBrown fat surrounds lymphatic systemBone marrow starts making blood cellsBone marrow starts making blood cellsInner Ear Bones HardenSensory brain waves begin to activateSensory brain waves begin to activateFetal liver is producing blood cellsBrain convolutions beginBrain convolutions beginImmune system beginningWhite fat begins to be madeHead may position into pelvisWhite fat begins to be madePeriod of rapid brain growthFull TermHead may position into pelvisImmune system beginningLungs begin to produce surfactant
CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development


Tracking development of individual blood stem cells

Harvard Stem Cell Institute (HSCI) researchers use a new cell-labeling technique to track development of adult blood cells to original stem cells in bone marrow — advancing our understanding of blood development and blood diseases.

Developed at Harvard's Center for Brain Science, the technique involves coding multiple florescent colors into proteins found in a cell's DNA. As genes recombine inside the cell, the cell reflects the colors unique to its genetic code.

For blood stem cells, color becomes a genetic signature passed down to daughter cells — purple stem cells will only make purple blood cells.

Two independent research teams, one led by David Scadden, HSCI co-director and Gerald and Darlene Jordan Professor of Medicine at Harvard University; the other by his colleague Leonard Zon, HSCI Executive Committee member and director of the Stem Cell Program at Boston Children's Hospital, together adapted color-based labeling to the blood system to better understand how blood stem cells behave.

In a study recently published in Nature Cell Biology, a team led by Scadden found that in mice individual blood stem cells had a specific and restricted blood production repertoire.

"We used to think of stem cells as the mother cell that gives rise to all these other cells in the system on an as needed basis," says Vionnie Yu, first author and postdoctoral fellow in Scadden's lab.

But results suggest stem cells are pre-scripted and cannot make just any blood cell type.

When transplanted into a new environment, each cell consistently made the same mature blood cell type — and also the same number of those cells.

Also, clones responded to inflammatory and chemotoxic stress similarly, suggesting cells have a memory dictating their behavior. Researchers found this memory written into the stem cell epigenome — the multitude of chemical compounds that tell the genome what to do.

Blood stem cells, said Scadden, may be more like chess pieces following a fixed path within the circulatory system.

"When you are young and have a full chess set you can mount a vigorous and multilayered defense to an attack on your system," Scadden adds, "but if you lose chess pieces with age or you don't receive a full suite of players during a bone marrow transplant, the pieces you have left could determine your ability to protect yourself."

In addition to looking at blood stem cells in adult mice, color tagging also allowed researchers to explore the zebrafish embryo blood system as it develops. Zon, who is also a professor in Harvard's Stem Cell and Regenerative Biology department, used the color tagging system to define the origin and number of stem cells that contribute to lifelong zebrafish blood production.

About 24 to 30 hours after fertilization, dozens of stem cells budded off from the dorsal side of the zebrafish aorta. Only twenty made it to a secondary site before heading to the kidney marrow, the zebrafish equivalent to human and mouse bone marrow.

After transplanting multicolored marrow into zebrafish that received sublethal doses of radiation, researchers found some blood stem cell lines give a greater proportion of blood than before, while other lines survived harsher conditions than before.

Knowing which cells are responsible for blood production helps in understanding how blood cancers develop, adds Jonathan Henninger, graduate student in Zon's lab, Boston Children's Hospital, and first author. For example, one blood stem cell could develop a mutation that gives it a competitive edge, allowing it to take over the blood system. "If that cell starts behaving badly, it could lead to blood disorders, such as myeloid dysplasia and leukemia," according to Henninger.

Although researchers know disorders come from a single stem cell or a downstream progenitor cell, Henninger says, right now they are looking at populations of stem cells in bulk: "To be able to identify that single cell that went awry could help us better understand these diseases."

Haematopoietic stem cells (HSCs) arise in the developing aorta during embryogenesis. The number of HSC clones born has been estimated through transplantation, but experimental approaches to assess the absolute number of forming HSCs in a native setting have remained challenging. Here, we applied single-cell and clonal analysis of HSCs in zebrafish to quantify developing HSCs. Targeting creERT2 in developing cd41:eGFP+ HSCs enabled long-term assessment of their blood contribution. We also applied the Brainbow-based multicolour Zebrabow system with drl:creERT2 that is active in early haematopoiesis to induce heritable colour barcoding unique to each HSC and its progeny. Our findings reveal that approximately 21 HSC clones exist prior to HSC emergence and 30 clones are present during peak production from aortic endothelium. Our methods further reveal that stress haematopoiesis, including sublethal irradiation and transplantation, reduces clonal diversity. Our findings provide quantitative insights into the early clonal events that regulate haematopoietic development.

Subject terms: Embryogenesis Haematopoiesis Haematopoietic stem cells Zebrafish

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Dec 2, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Florescently labeled and color coding of multiple proteins in Zebrafish, allows
Harvard researchers to track how they respond to transplantation or stress.

Image Credit:
Vionnie Yu, Zon Lab, Harvard University


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