Cell lineage

General stages of cell lineage (cell lineage of liver development in red)

Cell lineage denotes the developmental history of a tissue or organ from the fertilized egg.^[1] This is based on the tracking of an organism's cellular ancestry due to the cell divisions and relocation as time progresses, this starts with the originator cells and finishing with a mature cell that can no longer divide.^[2]

This type of lineage can be studied by marking a cell (with fluorescent molecules or other traceable markers) and following its progeny after cell division. Some organisms, such as C. elegans, have a predetermined pattern of cell progeny and the adult male will always consist of 1031 cells, this is because cell division in C. elegans is genetically determined and known as eutely.^[3]^[4] This causes the cell lineage and cell fate to be highly correlated. Other organisms, such as humans, have variable lineages and somatic cell numbers.

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- [Voiceover] So, let's draw a blood vessel. Here is a blood vessel. In any human, you or me, there's lots of different blood cells travelling around in all the blood vessels of the body. So, you've got your red blood cells, that I'm drawing here. But you've also got your T cells, which are immune cells. You've also got B cells. You've also got something called a macrophage. You've got neutrophils. You've got little platelets, which are actually fragments of cells, they don't have their own nucleoid. And, all in all, you actually have about 10 different kinds of blood cells. And a question you can ask, which is what we're gonna address in this video, is where do all these blood cells come from? Do you know? I'm gonna draw the answer right now and see if you can figure out what exactly I'm drawing. So, this is a bone. Because all these blood cells in the body come from the bone marrow. And here's the bone marrow that I'm drawing here. Now, actually it turns out that they don't come from all the bone marrow of the body. They come from certain places. Some of those places are the head of, for example, the femur, which is the long bone in your thigh. The head of the humerus, which is the long bone in your arm. Those are all long bones. And they also come from something called flat bones. These are very simple names, which I think is always good for us when we're learning a field. Flat bones, such as the one I'm drawing here, which is the sternum. The sternum is the flat bone in your body that connects to all the ribs. Here are some ribs. Of course, it has ribs on both sides. So, the blood cells come from these parts of the long bones and the flat bones of the body. And it turns out, which is interesting and which was not always known, it turns out that all these blood cells in your body have one common precursor, one grandfather, if you will. So, there's one grandfather cell that gives rise to all of these guys. And I'll draw him here. So, here he is. He's purple. His name is complicated. He's called a pluripotent. Pluripotent. If you ever took Latin, you might know that that means sort of able to do anything. Pluripotent hematopoietic stem cell. And the reason that he's called pluripotent is that he is able to give rise to any of the ten blood cells. So, hematopoietic stem cell. You might recall that stem cells are sort of undifferentiated cells that can give rise to many different kinds of cells. So, this grandfather cell gives rise to two different lineages. And those two lineages are the myeloid lineage and the lymphoid lineage. And each of these lineages gives rise to many different cells. The myeloid lineage gives rise to red blood cells, which are biconcave in shape. They are the most common of all blood cells. Now, the myeloid lineage also gives rise to a big cell called a megakaryocyte. Now, you might have never heard of this before, but the megakaryocytes themselves produce platelets, which I think that you've probably have heard of. So, here are platelets. They're little fragments of cells, which actually bud off of the megakaryocytes like this. They kind of squeeze out little pieces of cytoplasm that become platelets. And now I have a challenge for you. Do you think that a macrophage, which is an immune cell that likes to eat up invaders like bacteria, do you think that macrophages come from the myeloid lineage or the lymphoid lineage? So, I was surprised to find out that they actually come from the myeloid lineage. I was surprised because macrophages are immune cells, but they actually come from the same lineage as red blood cells and platelets. So here is a... This is actually not yet a macrophage, this is a monocyte. A lot of crazy words here, but this is a monocyte. Monocytes actually become macrophages once they settle down in the tissues. But, before that, while they're still circulating, they are monocytes. And, in addition to the monocyte, the myeloid lineage gives rise to three guys, one of whom you have heard of probably, two of whom you may not have heard of. I'll just draw them here. So, the one you might have heard of is the, I'm running out of space here, but it's the neutrophil. Neutrophils are the most common immune cell in the blood. The other two are called eosinophils, which are significantly more rare than neutrophils. And, even more rare than eosinophils, are something called the basophils. So, it's the three phils. So, now let's go over to the lymphoid lineage. There's three important cells that come from this one. Two of them you've probably heard of. I'll draw them first. They're both lymphocytes, so it makes sense that they come from the lymphoid lineage. And those are B cells and T cells. And if you recall, B cells are the guys that are going to put out this molecule. Do you know what that is? That's an antibody. B cells make antibodies. And T cells have their own functions that you can learn about in the immune system videos. Now, the lymphoid lineage also gives rise to something called, it actually has a very sort of die morbid name. It's called a natural killer cell. Sometimes, we say NK. Natural killer. So, this is pretty much it. Here we've got our grandfather cell, who gives rise to two lines. You could call these, maybe, the father cells, if you want. And these give rise to our whole array of blood cells. Some of them you've heard of, some of them you haven't. You'll hear more about the ones you haven't heard of in the future. There's one or two more I wanna mention now that are maybe a little more complicated. We have something called a dendritic cell. And the reason I didn't mention it before is because the dendritic cells actually come from both sides, both lineages, which is confusing. They can come from the lymphoid and they can come from the myeloid by way of monocytes. So, monocytes can become dendritic cells. And then we also have another one coming from the myeloid lineage, which is actually fairly important. I could have mentioned it earlier. It's called a mast cell. And mast cells are most notable for causing allergic reactions. They release histamine. You know when you have an allergic reaction you might take an anti-histamine and you do that so that these mast cells can't make you feel crummy.

C. elegans: model organism

As one of the first pioneers of cell lineage, in the 1960s Dr. Sydney Brenner first began observing cell differentiation and succession in the nematode Caenorhabditis elegans. Dr. Brenner chose this organism due to its transparent body, quick reproduction, ease of access, and small size which made it ideal for following cell lineage under a microscope.

By 1976, Dr. Brenner and his associate, Dr. John Sulston, had identified part of the cell lineage in the developing nervous system of C. elegans. Initial results showed that the nematode was eutelic (each individual experiences the same differentiation pathways), however work by Sulston and Richard Horvitz showed that several cells necessary for reproduction differentiate after hatching. These cells include vulval cells as well as muscle and neurons. This research also led to the initial observations of programmed cell death, or apoptosis.

After mapping various sections of the C. elegans' cell lineage, Dr. Brenner and his associates were able to piece together the first complete and reproducible fate map of cell lineage. They later received the 2002 Nobel prize for their work in genetic regulation of organ development and programmed cell death.^[5] Being that C. elegans are hermaphrodites, there consist of both male and female organs, where they store sperm and are able to self fertilize. C. elegans contain 302 neurons and 959 somatic cells, where they begin with 1031, where 72 undergo apoptosis which is programmed cell death. This makes C. elegans a model organism for studying cell lineage, and being able to observe the cell divisions due to their transparent phenotype.^[6]

History of cell lineage

One of the first studies of cell lineages took place in the 1870s by Whitman who studied cleavage patterns in leeches and small invertebrates. He found that some groups, such as nematode worms and ascidians form a pattern of cell division which is identical between individuals and invariable. This high correlation between cell lineage and cell fate was thought to be determined by segregating factors within the dividing cells. Other organisms had stereotyped patterns of cell division and produced sublineages which were the progeny of particular precursor cells. These more variable cell fates are thought to be due to the cells' interaction with the environment. Due to new breakthroughs in tracking cells with greater accuracy, this aided the biological community since a variety of colors are now used in showing the original cells and able to track easily. These colors are fluorescent and marked on the proteins by administering injections to trace such cells.^[7]

Techniques of fate mapping

Cell lineage can be determined by two methods, either through direct observation or through clonal analysis. During the early 19th century direct observation was used however it was highly limiting as only small transparent samples could be studied. With the invention of the confocal microscope this allowed larger more complicated organisms to be studied.^[8]

Perhaps the most popular method of cell fate mapping in the genetic era is through site-specific recombination mediated by the Cre-Lox or FLP-FRT systems. By utilizing the Cre-Lox or FLP-FRT recombination systems, a reporter gene (usually encoding a fluorescent protein) is activated and permanently labels the cell of interest and its offspring cells, thus the name cell lineage tracing.^[9] With the system, researchers could investigate the function of their favorite gene in determining cell fate by designing a genetic model where within a cell one recombination event is designed for manipulating the gene of interest and the other recombination event is designed for activating a reporter gene. One minor issue is that the two recombination events may not occur simultaneously thus the results need to be interpreted with caution.^[10] Furthermore, some fluorescent reporters have such an extremely low recombination threshold that they may label cell populations at undesired time-points in the absence of induction.^[11]

More recently, researchers have begun using synthetic biology approaches and the CRISPR/Cas9 system to engineer new genetic systems that enable cells to autonomously record lineage information in their own genome. These systems are based on engineered, targeted mutation of defined genetic elements.^[12]^[13] By generating new, random genomic alterations in each cell generation these approaches facilitate reconstruction of lineage trees. These approaches promise to provide more comprehensive analysis of lineage relationships in model organisms. Computational tree reconstruction methods^[14] are also being developed for datasets generated by such approaches.

Early developmental asymmetries

In humans after fertilization, the zygote divides into two cells. Somatic mutations that arise directly after the formation of the zygote, as well as later in development, can be used as markers to trace cell lineages throughout the body.^[15] Beginning with cleavages of the zygote, lineages were observed to contribute unequally to blood cells. As much as 90% of blood cells were found to be derived from just one of the first two blastomeres. In addition, normal development may result in unequal characteristics of symmetrical organs, such as between the left and right frontal and occipital cerebral cortex. It was proposed that the efficiency of DNA repair contributes to lineage imbalance, as additional time spent by a cell on DNA repair may decrease proliferation rate.^[15]

References

^ Collins English Dictionary - Complete & Unabridged 10th Edition. HarperCollins Publishers. Retrieved 2 June 2014.
^ Giurumescu, Claudiu A.; Chisholm, Andrew D. (2011). "Cell Identification and Cell Lineage Analysis". Methods in Cell Biology. 106: 325–341. doi:10.1016/B978-0-12-544172-8.00012-8. ISBN 9780125441728. ISSN 0091-679X. PMC 4410678. PMID 22118283.
^ Sulston, JE; Horvitz, HR (1977). "Post-embryonic cell lineages of the nematode, Caenorhabditis elegans". Developmental Biology. 56 (1): 110–56. doi:10.1016/0012-1606(77)90158-0. PMID 838129.
^ Kimble, J; Hirsh, D (1979). "The postembryonic cell lineages of the hermaphrodite and male gonads in Caenorhabditis elegans". Developmental Biology. 70 (2): 396–417. doi:10.1016/0012-1606(79)90035-6. PMID 478167.
^ "The Nobel Prize in Physiology or Medicine for 2002 - Press Release". www.nobelprize.org. Retrieved 2015-11-23.
^ Corsi, Ann K. (2006-12-01). "A Biochemist's Guide to C. elegans". Analytical Biochemistry. 359 (1): 1–17. doi:10.1016/j.ab.2006.07.033. ISSN 0003-2697. PMC 1855192. PMID 16942745.
^ Woodworth, Mollie B.; Girskis, Kelly M.; Walsh, Christopher A. (April 2017). "Building a lineage from single cells: genetic techniques for cell lineage tracking". Nature Reviews. Genetics. 18 (4): 230–244. doi:10.1038/nrg.2016.159. ISSN 1471-0056. PMC 5459401. PMID 28111472.
^ Chisholm, A D (2001). "Cell Lineage" (PDF). Encyclopedia of Genetics. pp. 302–310. doi:10.1006/rwgn.2001.0172. ISBN 9780122270802.^{[permanent dead link]}
^ Kretzschemar, K; Watt, F.M. (Jan 12, 2012). "Lineage tracing". Cell. 148 (1–2): 33–45. doi:10.1016/j.cell.2012.01.002. PMID 22265400.
^ Liu, J; Willet, SG; Bankaitis, ED (2013). "Non-parallel recombination limits Cre-LoxP-based reporters as precise indicators of conditional genetic manipulation". Genesis. 51 (6): 436–42. doi:10.1002/dvg.22384. PMC 3696028. PMID 23441020.
^ Álvarez-Aznar, A.; Martínez-Corral, I.; Daubel, N.; Betsholtz, C.; Mäkinen, T.; Gaengel, K. (2020). "Tamoxifen-independent recombination of reporter genes limits lineage tracing and mosaic analysis using CreERT2 lines". Transgenic Research. 29 (1): 53–68. doi:10.1007/s11248-019-00177-8. ISSN 0962-8819. PMC 7000517. PMID 31641921.
^ McKenna, Aaron; Findlay, Gregory M.; Gagnon, James A.; Horwitz, Marshall S.; Schier, Alexander F.; Shendure, Jay (2016-07-29). "Whole-organism lineage tracing by combinatorial and cumulative genome editing". Science. 353 (6298): aaf7907. doi:10.1126/science.aaf7907. ISSN 0036-8075. PMC 4967023. PMID 27229144.
^ Frieda, Kirsten L.; Linton, James M.; Hormoz, Sahand; Choi, Joonhyuk; Chow, Ke-Huan K.; Singer, Zakary S.; Budde, Mark W.; Elowitz, Michael B.; Cai, Long (2017). "Synthetic recording and in situ readout of lineage information in single cells". Nature. 541 (7635): 107–111. Bibcode:2017Natur.541..107F. doi:10.1038/nature20777. PMC 6487260. PMID 27869821.
^ Zafar, Hamim; Lin, Chieh; Bar-Joseph, Ziv (2020). "Single-cell lineage tracing by integrating CRISPR-Cas9 mutations with transcriptomic data". Nature Communications. 11 (3055): 3055. Bibcode:2020NatCo..11.3055Z. doi:10.1038/s41467-020-16821-5. PMC 7298005. PMID 32546686.
^ ^a ^b Fasching L, Jang Y, Tomasi S, Schreiner J, Tomasini L, Brady MV, Bae T, Sarangi V, Vasmatzis N, Wang Y, Szekely A, Fernandez TV, Leckman JF, Abyzov A, Vaccarino FM (19 March 2021). "Early developmental asymmetries in cell lineage trees in living individuals". Science. 371 (6535): 1245–1248. Bibcode:2021Sci...371.1245F. doi:10.1126/science.abe0981. PMC 8324008. PMID 33737484.

This page was last edited on 6 May 2024, at 14:32

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