Stem Cells

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Introduction

Human Blastocyst (Carnegie Stage 3)

The term "stem cell" is used so freely these days in many different forums that it is difficult sometimes understand without context what scientists, politicians, ethicists and commentators are discussing. In terms of human development, the embryonic stem cell with totipotential occurs at the blastocyst stage, mainly in the first and second week of development. After this period the inner cell mass, which forms the entire embryo, will differentiate into embryonic germ layers with restricted differentiation potential.

Stem cells as well as having the capacity to differentiate into any (totipotential) or multiple (pluripotential) cell types, have the unique capacity of self-renewal.

In vitro fertilization and growth of the blastocyst, allows isolation of these cells and their subsequent use in stem cell research. It is the collection, production and possible therapeutic applications of these stem cells which has recently attracted worldwide attention.

Mice cloned from adult keratinocytes[1]

A key step in the development of stem cell research has been the identification of cell surface markers (proteins) which identify these cells and their state of undifferentiation.

NIH Information

A useful guide (online PDF document) to stem cells was produced in a report by the National Institute of Health (NIH, USA, April 2009) Stem Cells: A Primer (PDF 1.89 MB) and more recently NIH has established a Stem Cell information page.

Stem Cells: NIH 2009 Primer | File:NIH Regenerative Medicine 2006.pdf | 2001 Primer | NIH Stem Cell Basics | 2009 NIH Report | Regenerative Medicine 2006 | 2001 NIH Report


Stem Cell Links: Introduction | Timeline | Placental Cord Blood | Adult | Induced pluripotent stem cell | Yamanaka Factors | Somatic Cell Nuclear Transfer | Ethics | Organoids | Adult Human Cell Types | Category:Stem Cell

Some Recent Findings

Human stem cell pancreas implants
Human stem cell pancreas implants[2]
human blastocyst
Stem cell artificial trachea and bronchi (Image UCL)
  • Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice[2] "The transplantation of glucose-responsive, insulin-producing cells offers the potential for restoring glycemic control in individuals with diabetes. Pancreas transplantation and the infusion of cadaveric islets are currently implemented clinically, but these approaches are limited by the adverse effects of immunosuppressive therapy over the lifetime of the recipient and the limited supply of donor tissue. The latter concern may be addressed by recently described glucose-responsive mature beta cells that are derived from human embryonic stem cells (referred to as SC-β cells), which may represent an unlimited source of human cells for pancreas replacement therapy. ...human SC-β cells were encapsulated with alginate derivatives capable of mitigating foreign-body responses in vivo and implanted into the intraperitoneal space of C57BL/6J mice treated with streptozotocin, which is an animal model for chemically induced type 1 diabetes. These implants induced glycemic correction without any immunosuppression until their removal at 174 d after implantation. Human C-peptide concentrations and in vivo glucose responsiveness demonstrated therapeutically relevant glycemic control. Implants retrieved after 174 d contained viable insulin-producing cells."
  • Haematopoietic stem cell induction by somite-derived endothelial cells controlled by meox1[3] Haematopoietic stem cells (HSCs) are self-renewing stem cells capable of replenishing all blood lineages. In all vertebrate embryos that have been studied, definitive HSCs are generated initially within the dorsal aorta (DA) of the embryonic vasculature by a series of poorly understood inductive events. Previous studies have identified that signalling relayed from adjacent somites coordinates HSC induction, but the nature of this signal has remained elusive. Here we reveal that somite specification of HSCs occurs via the deployment of a specific endothelial precursor population, which arises within a sub-compartment of the zebrafish somite that we have defined as the endotome. Endothelial cells of the endotome are specified within the nascent somite by the activity of the homeobox gene meox1. Specified endotomal cells consequently migrate and colonize the DA, where they induce HSC formation through the deployment of chemokine signalling activated in these cells during endotome formation." Blood Development
More recent papers  
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Search term: Stem Cells

<pubmed limit=5>Stem Cells</pubmed>

Older papers  
  • Generation of organized germ layers from a single mouse embryonic stem cell[4] "Mammalian inner cell mass cells undergo lineage-specific differentiation into germ layers of endoderm, mesoderm and ectoderm during gastrulation. It has been a long-standing challenge in developmental biology to replicate these organized germ layer patterns in culture. Here we present a method of generating organized germ layers from a single mouse embryonic stem cell cultured in a soft fibrin matrix." Gastrulation
  • Derivation of naive human embryonic stem cells[5] "We show that human naïve cells meet mouse criteria for the naïve state by growth characteristics, antibody labeling profile, gene expression, X-inactivation profile, mitochondrial morphology, microRNA profile and development in the context of teratomas. hESCs can exist in a naïve state without the need for transgenes. Direct derivation is an elusive, but attainable, process, leading to cells at the earliest stage of in vitro pluripotency described for humans. Reverse toggling of primed cells to naïve is efficient and reproducible."
  • Human Embryonic Stem Cells Derived by Somatic Cell Nuclear Transfer [6] 1. Cytoplasm of human oocytes reprograms transplanted somatic cell nuclei to pluripotency. 2. NT-ESCs can be efficiently derived from high-quality human oocytes 3. Human NT-ESCs are similar to ESCs derived from fertilized embryos. Nature comment - Human stem cells created by cloning
  • The Nobel Prize in Physiology or Medicine 2012 was awarded jointly to Sir John B. Gurdon and Shinya Yamanaka "for the discovery that mature cells can be reprogrammed to become pluripotent" Shinya Yamanaka Yamanaka Factors are a set of 4 transcription factors when introduced into cells induces stem cell formation. John Gurdon used nuclear transplantation and cloning to show that the nucleus of a differentiated somatic cell retains the totipotency necessary to form a whole organism. Induced Stem Cells
  • Stem Cell Treatment for Eye Disease Sydney April 2012 Meeting Program See also Vision Development.
  • Nature Cell Biology Focus on stem cells "This issue presents a series of specially commissioned articles that highlight exciting facets of stem cell research, including recent insights into the nature of pluripotency and how studying stem cells can increase our understanding of normal ageing and disease." Editorial
  • First Successful Transplantation of a Synthetic Tissue Engineered Windpipe Karolinska Institute | University College London | BBC News "An international team designed and built the nanocomposite tracheal scaffold and produced a specifically designed bioreactor used to seed the scaffold with the patient´s own stem cells. The cells were grown on the scaffold inside the bioreactor for two days before transplantation to the patient. Because the cells used to regenerate the trachea were the patient's own, there has been no rejection of the transplant and the patient is not taking immunosuppressive drugs."
  • Culture of human pluripotent stem cells using completely defined conditions on a recombinant E-cadherin substratum[7] "huES and human induced pluripotent stem (hiPS) cells were grown on plates coated with a fusion protein consisting of E-cadherin and the IgG Fc domain using mTeSR1 medium. Cells grown under these conditions maintained similar morphology and growth rate to those grown on Matrigel and retained all pluripotent stem cell features, including an ability to differentiate into multiple cell lineages in teratoma assays."
  • Epigenetic memory in induced pluripotent stem cells. [8] "Our data indicate that nuclear transfer is more effective at establishing the ground state of pluripotency than factor-based reprogramming, which can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modelling or treatment."

Embryonic Stem Cell

Human blastocyst derived stem cells.jpg

Human blastocyst derived stem cells[9]

(A–D) - stepwise procedure of embryo biopsy using inverted microscope-attached micro manipulator.

(E–L) - appearance of initial outgrowth and hESC colony during the derivation procedure.

Cord Blood Stem Cell

Placental cord blood is a rich souce of haematopoietic stem cells for transplantation. Cord blood can collected at birth, with no impact on the mother or neonate, and stured in cord blood banks for later use. BBC (UK) A brief article on Cord Blood stem cells and their therapeutic potential.

Links: Stem Cells - Placental Cord Blood

Spermatogonial Stem Cell (SSC)

In the male testes are a population of spermatogonia cells that differentiate and meiotically divide to form spermatozoa cells (male germ cells).

  • Production of knockout mice by random or targeted mutagenesis in spermatogonial stem cells.[10]
  • Spermatogonial stem cells: questions, models and perspectives.[11]
  • [Spermatogonial stem cells: characteristics and experimental possibilities.[12]
  • Genetic and epigenetic properties of mouse male germline stem cells during long-term culture.[13]
  • Expansion of murine spermatogonial stem cells through serial transplantation.[14]


Adult Stem Cell

Epidermis - stem cell models[15]

Adult stem cells, with pluropotentiality, are found in several body systems: intestinal epithelium, epidermis, testis and bone marrow.

  • Generation of pluripotent stem cells from adult human testis[16]"Human primordial germ cells and mouse neonatal and adult germline stem cells are pluripotent and show similar properties to embryonic stem cells. Here we report the successful establishment of human adult germline stem cells derived from spermatogonial cells of adult human testis."


Links: Stem Cells - Adult

Inducible Stem Cells

Inducible pluripotent stem cells (iPS) require a minimum of key defined transcription factors (Oct3/4, Sox2, Klf4, c-Myc, Nanog and Lin28) are required to be introduced into a cell to "induce" that cell to revert to a stem cell phenotype.

  • Induction of pluripotent stem cells from adult human fibroblasts by defined factors.[17]
  • Generation of induced pluripotent stem cells by reprogramming mouse embryonic fibroblasts with a four transcription factor, doxycycline inducible lentiviral transduction system.[18]


Links: Stem Cells - Induced

Nuclear Transfer

Dolly the Sheep

This technique involves removing the nucleus from an early stage embryo and replacing with the nucleus from another cell. If the replacement nucleus is from a somatic cell, not a gamete, the technique is also described as somatic cell nuclear transfer (SCNT). The most famous of which was the sheep "Dolly". More recently nuclei have been sourced from a number of different tissues, including those from long-term frozen animals.[19]

For a recent review of this technique see.[20]


Links: Somatic Cell Nuclear Transfer | Stem Cells - SCNT

Stem Cell Regulation

Mouse- embryonic stem cell signaling regulation.jpg

Embryonic stem cell signaling regulation (mouse)[21]

Stem Cell Markers

Bovine stem cell marker expression[22]

In order to carry out research on stem cells, it is important to be able to identify them. A number of different research groups in the late 90's generated several antibodies which specifically identified undifferentiated, differentiating or differentiated stem cells from a number of different sources and species. Note that the nomenclature in some cases is based upon the antibody used to identify the cell surface marker.

  • Stage-Specific Embryonic Antigen-1 (SSEA-1) cell surface embryonic antigen which has a role in cell adhesion, migration and differentiation and is often differentially expressed during development. Can be identified by Davor Solter (monoclonal antibody MC-480) (SSEA-1).
  • Stage-Specific Embryonic Antigen-4 (SSEA-4) cell surface embryonic antigen of human teratocarcinoma stem cells (EC), human embryonic germ cells (EG) and human embryonic stem cells (ES) which is down-regulated following differentiation of human EC cells. Antigen not expressed on undifferentiated murine EC, ES and EG cells but upregulated on differentiation of murine EC and ES cells. Can be identified by Davor Solter (monoclonal antibody MC-813-70) (SSEA-4)
  • Tumor Rejection Antigen (TRA-1-60) Sialylated Keratan Sulfate Proteoglycan expressed on the surface of human teratocarcinoma stem cells (EC), human embryonic germ cells (EG) and human embryonic stem cells (ES).
  • Tumor Rejection Antigen (TRA-1-81) antigen expressed on the surface of human teratocarcinoma stem cells (EC), human embryonic germ cells (EG) and human embryonic stem cells (ES). Both TRA antibodies identify a major polypeptide (Mr 240 kDa) and a minor polypeptide (Mr 415 kDa).
  • Oct-4 (Pou5f1) gene has an essential role in control of developmental pluripotency (Oct4 knockout embryo blastocysts die at the time of implantation). Oct4 also has a role in maintaining viability of mammalian germline.
  • Stem Cell Antigen 1 (Sca-1) member of the Ly-6 family of GPI-linked surface proteins (Mr 18 kDa) and a major phenotypic marker for mouse hematopoietic progenitor/stem cell subset.
  • CD133, AC133, prominin 5 transmembrane glycoprotein (865 aa) expressed on stem cells with hematopoietic and nonhematopoietic differentiation potential.
  • Alpha 6 integrin


Data based on information from Appendix E.II. NIH Report "Stem Cells: Scientific Progress and Future Research Directions", Chemicon International- Stem cell marker antibodies OMIM and other sources.

Human embryonic stem cell

A recent paper identified the expression pattern of a new human embryonic stem cell line (hESC).[23]

  • alkaline phosphatase
  • human telomerase reverse transcriptase
  • SSEA-3, SSEA-4
  • TRA-1-60, TRA-1-81
  • OCT-4, Nanog
  • Rex-1, Sox-2, UTF-1, Connexins 43 and 45
  • TERF-1 and TERF-2
  • Glut-1, BCRP-1/ABCG-2, GDF3, LIN28, FGF4, Thy-1
  • Cripto1/TDGF1, AC133
  • SMAD1/2/3/5

Opinion on Stem Cell Use

Results from a recent Australian survey into couples' views on the use of supernumerary embryos:[24]

  • 40% (123/311) returned completed questionnaires.
  • 42% most common decision was donation to research (altruistic motives and desire not to waste embryos were determinants of embryo donation).

Determinants of disposal were not wanting a full sibling to existing children and opposition of embryo research.

  • 45% found deciding distressing.
  • 69% approved of embryo donation to stem-cell research.


Stem Cell Fake Result

Hwang Woo-suk (Korean pioneer of stem cell research) Resigns A Seoul National University investigation of the original data in Science paper Jun (2005;308: 1777-83) "Eleven human embryonic stem cells (hESC) lines were established by nuclear transfer (SCNT; NT) of skin cells from patients with disease or injury into donated oocytes." announced 29 Dec 2005 that he had faked the results.

The journal Science retracted the original paper, the original reference with link to the erratum.[25]

Science News 06 Jan | Special Online Collection: Hwang et al. and Stem Cell Issues

Cancer

There is a hypothesis that several cancers may arise from somatic stem or progenitor cells that exist in different tissues. These cancer stem cells are called "side population" (SP) cells and have been identified in: leukemia, breast cancer and several human cancer cell lines (central nervous system, gastrointestinal tumors, retinoblastoma). There is still a "chicken and egg" problem to be resolved, in that the cancer cells may have dedifferentiated to a stem cell-like population.

A recent paper has also identified SP cells in ovarian cancer which have properties similar to stem cells.[26]

References

  1. ↑ <pubmed>17299040</pubmed>| PMC1815251
  2. ↑ 2.0 2.1 <pubmed>26808346</pubmed>
  3. ↑ <pubmed>25119043</pubmed>
  4. ↑ <pubmed>24873804</pubmed>
  5. ↑ <pubmed>24623855</pubmed>
  6. ↑ Human Embryonic Stem Cells Derived by Somatic Cell Nuclear Transfer Cell May 2013.
  7. ↑ <pubmed>20525219</pubmed>
  8. ↑ <pubmed>20644535</pubmed>
  9. ↑ Giritharan G, Ilic D, Gormley M, Krtolica A. Human embryonic stem cells derived from embryos at different stages of development share similar transcription profiles. PLoS One. 2011;6(10):e26570. PMID 22039509| PLoS One.
  10. ↑ <pubmed>16679411</pubmed>
  11. ↑ <pubmed>16446319</pubmed>
  12. ↑ <pubmed>16480445</pubmed>
  13. ↑ <pubmed>16107472</pubmed>
  14. ↑ <pubmed>12493728</pubmed>
  15. ↑ <pubmed>18209104</pubmed>JCB
  16. ↑ <pubmed>18849962</pubmed>
  17. ↑ <pubmed>18035408</pubmed>
  18. ↑ <pubmed>19915522</pubmed>
  19. ↑ <pubmed>18981419</pubmed>
  20. ↑ <pubmed>20203432</pubmed>
  21. ↑ <pubmed>20875146</pubmed>| PMC2946285 | BMC Biol.
  22. ↑ <pubmed>22479535</pubmed>| PMC3315523 | PLoS ONE
  23. ↑ <pubmed>20973834</pubmed>
  24. ↑ <pubmed>16716313</pubmed>
  25. ↑ <pubmed>15905366</pubmed>
  26. ↑ <pubmed>16574858</pubmed>

Journals

  • Cell Stem Cell is the official affiliated journal of the International Society for Stem Cell Research (ISSCR).
  • Stem Cells welcomes original articles and concise reviews describing basic laboratory investigations of stem cells and the translation of their clinical aspects of characterization and manipulation from the bench to patient care. The journal covers all aspects of stem cells: embryonic stem cells; tissue-specific stem cells; cancer stem cells; the stem cell niche; stem cell genomics and proteomics; and translational and clinical researc

Reviews

<pubmed>26908143</pubmed> <pubmed>19570509</pubmed> <pubmed>16574858</pubmed> <pubmed>16212509</pubmed>

Articles

<pubmed>20369364</pubmed> <pubmed>16728281</pubmed> <pubmed>16723974</pubmed> <pubmed>16719047</pubmed> <pubmed>16716780</pubmed> <pubmed>16716313</pubmed> <pubmed>16574858</pubmed>

Search PubMed

May 2006 "stem cell" 154,176 reference articles of which 16,449 were reviews.

Search PubMed Now: stem cell | embryonic stem cell | adult stem cell |

Australia

The Australian Health Ethics Committee was approached by human research ethics committees (HRECs) seeking advice on how to review research protocols that involve stem cell research. The following guidance is interim. Formal guidelines will be developed by AHEC in the context of its review of the 1996 NHMRC Ethical guidelines on assisted reproductive technology.

INFORMATION FOR HUMAN RESEARCH ETHICS COMMITTEES SHEET NUMBER 5 - STEM CELL RESEARCH

USA

Stem Cells: NIH 2009 Primer | File:NIH Regenerative Medicine 2006.pdf | 2001 Primer | NIH Stem Cell Basics | 2009 NIH Report | Regenerative Medicine 2006 | 2001 NIH Report

National Institute of Health (NIH) Stem Cell Information NIH Stem Cell Basics | NIH Stem Cell Information | NIH Stem Cell Reports | Regenerative Medicine 2006 | Stem Cells: Scientific Progress and Future Research Directions (2001) | National Human Genome Research Institute - Cloning/Embryonic Stem Cells

Stem Cell News (2001)

During the earlier Bush administration there was much political controversy about Stem cells in the USA.

External Links

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Cite this page: Hill, M.A. (2024, April 23) Embryology Stem Cells. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Stem_Cells

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