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Subtype-specific Stem Cell and Differentiation Markers


Introduction of Subtype-specific Stem Cell and Differentiation Markers

Subtype-specific Stem Cell and Differentiation Markers

The so-called subtype-specific stem cells are one kind of cells before they are differentiated into stem cells. For example, adult contain very small numbers of hematopoietic stem cells, the amount of stem cells in the blood of an infant’s cord is high, but the amount of a baby is often insufficient for treating adults. The long-term supply of clinical hematopoietic stem cells has made many patients lose the opportunity to cure diseases and survive. The process of hematopoietic begins in the early stages of embryonic development and runs through the living body lifelong. There are many coordination and antagonism between many signal pathways and regulatory factors in this process. These regulate hematopoietic stem cell production, maintenance, differentiation and self-renewal. Therefore, a comprehensive understanding of the regulatory mechanisms in the process of hematopoiesis has important guiding significance for the acquisition of hematopoietic stem cells and regenerative medicine in vitro.

Regulation of Differentiation Process

We still use the differentiation process of hematopoietic stem cells to illustrate. The hematopoietic origin of vertebrates originates from the ventral mesoderm, and some of the cells are specialized to form hemangio-blast precursor cells, this cell has the ability to differentiate into blood and vascular precursor cells. The transcription factor Etv2 (Er71/Etsrp) is the master gene in the process of mesoderm to hematopoietic progenitor cells, and regulates development of blood and blood vessels. During the development of vascular precursor cells, Etv2 is regulated by FLK1 and affects the development of mesoderm; moreover, during subsequent vascular development, Etv2 regulates its transcription by direct binding to the flk1 promoter region. Mouse experiments demonstrated that Etv2 is located downstream of BMP, Notch and Wnt signaling to regulate blood vessel progenitor cell fate determination. At this point we still can’t it a subtype-specific stem cell. From the initial embryo to the formation of stem cells are all controlled by the step-by-step regulation of the signaling pathway. In the regulation of vascular development, especially in the arterial development signaling pathway, more research is on the VEGF signaling pathway. After binding to the receptor Kdrl expressed by endothelial cells, the VEGFa signal produced in the somite is transmitted to the endothelial cells, thereby regulating arterial differentiation through the downstream ERK signaling pathway. ERK signaling pathways are time and concentration-dependent. Deletion of ERK signaling prior to angiogenesis leads to incomplete arterial development, which ultimately leads to the hematopoietic stem cells produce; excessive ERK signaling after angiogenesis promotes the maintenance of arterial endothelial properties. At the same time, the tight junction between the arterial endothelium is enhanced by up-regulating the expression of the endothelial-specific adhesion molecule ESAM, which is also detrimental to the production of hematopoietic stem cells. Therefore, in order to ensure the smooth production of hematopoietic stem cells, the ERK signaling pathway needs to be strictly controlled.

Key Transcription Factors During Differentiation

There are a series of genes and signaling pathways that influence the endothelial-hematopoietic transition (EHT) process, and three of these genes have been shown to be directly involved in this process. The scl gene is one of the earlist marker genes for blood and vascular precursor cells. In scl knockout mice and zebrafish embtyos, primary hematopoiesis and secondary hematopoiesis are absent. Research on zebrafish found that scl is an indispensable factor in the fate of blood-derived endothelial cells. Subsequent studies revealed two scl transcripts: sclα and sclβ, where sclβ is expressed before the EHT process, and then sclα is expresses in newly produced hematopoietic stem cells. Functional loss experiments have shown that the loss of sclβ leads to the inability of the hematopoietic endothelium to undergo endothelial hematopoietic transformation, suggesting that sclβ can regulating the development of hematopoietic stem cells; while sclα plays a role in the maintenance of newly formed hematopoietic stem cells. In the stage of hematopoietic stem cell formation, Gate2 is expressed in the aorta and umbilical arteries of mouse embryos, as well as intravascular blood cell clusters. And gata2-deficient mouse embryos die before hematopoietic stem cells (E10), suggesting that gata2 may play a role in the development of hematopoietic stem cells. The expression of gata2 in the AGM region is dependent on the cis-acting element (+9.5). the knockout of this enhancer region results in a decrease in the expression levels of the hematopoietic key genes (runx2 and scl) in AGM region, and results in the inability of the hematopoietic endothelium to produce hematopoiesis stem cells through the EHT process. In addition, some transcription factors affect the secondary hematopoietic process by regulating the expression of key genes that determine the fate of hematopoietic stem cells, such as scl, runx1.

Obstacles in Clinical Application

The process of hematopoiesis is an important life activity in the process of embryonic development, it can produce a variety of mature blood cells, which are regulated by multiple factors and involve multiple hematopoietic tissues. Hematopoietic stem cells are the original progenitor cells of all blood cells. Their normal development and differentiation are important conditions for ensuring the normal hematopoietic process of the body. There are intricate dynamic regulatory networks during the development of hematopoietic stem cells. Any link change of regulating networks, the hematopoietic process will a series of changes have followed, leading to serous developmental defects or majors diseases. How to obtain transplantable and functional hematopoietic stem cells from outside the body has been an urgent problem in the field of stem cells.

References:

  1. Schweizer Patrick A, Darche Fabrice F, Ullrich Nina D et al. Subtype-specific differentiation of cardiac pacemaker cell clusters from human induced pluripotent stem cells. Stem Cell Res Ther. 2017, 8(1): 229.
  2. Nédelec Stéphane, Peljto Mirza, Shi Peng et al. Concentration-dependent requirement for local protein synthesis in motor neuron subtype-specific response to axon guidance cues. J. Neurosci. 2012, 32(4): 1496-506.
  3. Takiguchi-Hayashi K. In vitro clonal analysis of rat cerebral cortical neurons expressing latexin, a subtype-specific molecular marker of glutamatergic neurons. Brain Res. Dev. Brain Res. 2001, 132(1): 87-90.
  4. Hall Amelia Weber, Battenhouse Anna M, Shivram Haridha et al. Bivalent Chromatin Domains in Glioblastoma Reveal a Subtype-Specific Signature of Glioma Stem Cells. Cancer Res. 2018, 78(10): 2463-2474.
  5. Marczenke Maike, Piccini Ilaria, Mengarelli Isabella et al. Cardiac Subtype-Specific Modeling of K1.5 Ion Channel Deficiency Using Human Pluripotent Stem Cells. Front Physiol. 2017, 8: 469.
  6. Hu Bao-Yang, Zhang Su-Chun. Directed differentiation of neural-stem cells and subtype-specific neurons from hESCs. Methods Mol. Biol. 2010, 636: 123-37.
  7. Cvoro Aleksandra, Bajic Aleksandar, Zhang Aijun et al. Ligand Independent and Subtype-Selective Actions of Thyroid Hormone Receptors in Human Adipose Derived Stem Cells. PLoS ONE. 2016, 11(10): e0164407.

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