Stem Cells and Cellular Development By C. Kohn Dept. of Agricultural Sciences, Waterford WI Stem Cells and Cellular Development

Questions How does a single cell—the fertilized egg—give rise to a complex, multicellular organism? Scientific understanding on cellular development is far from complete. However, scientists are beginning to understand how a single cell can become the 100 trillion cells that make up your body.

Stages of Cell Development What we do know: 1. A sperm cell fertilizes an egg cell, creating the first cell of the body. 2. The fertilized egg divides; this is called cleavage 3. The cleaving cells form a ball of cells (a morula) 4. The morula (ball of cells) will become hollow ball The hollow ball of cells is called a blastocyst cathylaw.com

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Inner Cell Mass & Germ Layers The blastocyst will form a clup of cells inside the hollow ball. These cells are called the Inner Cell Mass (ICM) When the ICM forms, it will have three layers. Each layer will become a specific kind of tissue in the body. These three layers are known as germ layers The three germ layers are… Ectoderm (outside) Mesoderm (middle) Endoderm (inside) dimitrismargaris.com

ICM Germ Layers Each of the three germ layers of the Inner Cell Mass becomes a specific kind of tissue. The ectoderm will become the nerve cells, skin cells, spinal cord, and brain The mesoderm becomes the blood, muscle, and bone cells. The endoderm becomes the gut, bladder, liver, pancreas, and lungs. dimitrismargaris.com

Stem Cells So why do germ layers matter? The ectoderm, mesoderm, and endoderm in the Inner Cell Mass are what create stem cells. Stem cells are cells that can differentiate into any kind of cell in the body. telegraph.co.uk

Stem Cells 101 Stem cells are cells that can develop into many different cell types in the body during early life and during growth. Additionally, they divide without limit to replace other cells as they die or are lost in adults. When a stem cell divides, each new cell has the potential to either a) remain a stem cell or b) become another type of cell with a more specialized function (such as a muscle cell, a red blood cell, or a brain cell). Source: National Institute of Health townipproject.wikispaces.com

Stem Cells 101 Stem cells are distinguished from other cell types by two important characteristics. First, they are unspecialized cells (they don’t have a specific function in the body) Stem cells are capable of renewing themselves through cell division, even after long periods of inactivity. Second, under certain conditions, they can be induced to become cells with special functions (such as heart cells or nerves) In some organs, such as the gut and bone marrow, stem cells regularly divide to repair and replace worn out or damaged tissues. In other organs, however, such as the pancreas and the heart, stem cells only divide under special conditions. Source: National Institute of Health amyshah.com

Kinds of Stem Cells Typically, stem cells are categorized into two groups: 1. Embryonic Stem Cells – these come from leftover fertilized eggs donated by fertilization clinics with the consent of the patients. 2. Adult (or somatic) Stem Cells – these are rare undifferentiated cell found in many organs and in adults with a limited capacity for both self renewal (in the laboratory) and differentiation. Such cells vary in their differentiation capacity, but it is usually limited to cell types in the organ of origin. Source: National Institute of Health

Regenerative Medicine Because stem cells can become any kind of tissue in the body, they offer new options for treating diseases such as diabetes and heart disease. However, much work remains to be done in the laboratory and the clinic to understand how to use these cells for cell-based therapies to treat disease The use of stem cells as medicine is referred to as regenerative or reparative medicine. Source: National Institute of Health duq.edu

Properties of Stem Cells Stem cells differ from other types of cells in the body. All stem cells—regardless of their source—have three general properties: 1) they are capable of dividing and renewing themselves for long periods 2) they are unspecialized, and… 3) they can give rise to specialized cell types. Source: National Institute of Health

Indefinite Cell Renewal Regular cells cannot divide forever – eventually they will stop dividing. Stem cells are capable of dividing and renewing themselves for long periods. Unlike muscle cells, blood cells, or nerve cells—which do not normally replicate themselves—stem cells may replicate many times, or proliferate. A starting population of stem cells that proliferates for many months in the laboratory can yield millions of cells. If the resulting cells continue to be unspecialized, like the parent stem cells, the cells are said to be capable of long-term self-renewal. Source: National Institute of Health humansfuture.org

Stem Cell Unknowns Scientists are trying to understand two fundamental properties of stem cells that relate to their long-term self-renewal: 1. Why can embryonic stem cells proliferate for a year or more in the laboratory without differentiating, but most non-embryonic stem cells (adult stem cells) cannot; and … 2. What factors in living organisms normally regulate stem cell proliferation (cell division) and self-renewal? The answers to these questions may make it possible to understand how cell proliferation is regulated during both normal human development as well as in diseases like cancer. Such information would also enable scientists to grow embryonic and non-embryonic stem cells more efficiently in the laboratory. This could lead to the production of organs for transplant patients and tissues for testing medication, among other technologies. Source: National Institute of Health

Stem Cell Trial & Error It has taken many years of trial and error to learn to derive and maintain stem cells in the laboratory without them spontaneously differentiating into specific cell types. For example, it took two decades to learn how to grow human embryonic stem cells in the laboratory following the development of conditions for growing mouse stem cells. The signals in a mature organism that cause a stem cell population to remain unspecialized until the cells are needed are still not fully understood Such information is critical for scientists to be able to grow large numbers of unspecialized stem cells in the laboratory for further experimentation. Source: National Institute of Health

Stem Cell Timeline 1981: Embryonic stem cells are first isolated in mice by two groups — Gail Martin at the University of California, San Francisco, and Martin Evans, then with the University of Cambridge November 1995: Researchers at the University of Wisconsin isolate the first embryonic stem cells in primates — rhesus macaque monkeys. The research shows it's possible to derive embryonic stem cells from primates, including humans. Nov. 5, 1998: Researchers at the University of Wisconsin and Johns Hopkins University report isolating human embryonic stem cells. The cells have the potential to become any type of cell in the body and might one day be used to replace damaged or cancerous cells Taken from NPR’s Key Moments in the Stem-Cell Debate

Stem Cell Timeline Aug. 9, 2001: President Bush announces his decision to limit funding to a few dozen lines of embryonic stem cells in existence at that date. Many of the approved lines later prove to be contaminated, and some contain genetic mutations, making them unsuitable for research. Nov. 25, 2001: Scientists at Advanced Cell Technology in Massachusetts claim to have cloned a human embryo. However, the evidence proves controversial and not conclusive. Feb. 12, 2004: South Korean scientists announce the world's first successfully cloned human embryo. The embryos were cloned not for reproductive purposes but as a source of stem cells. Jan. 10, 2006: The Seoul National University investigation concludes that the landmark 2004 paper was fabricated. May 12, 2006: South Korean scientist Hwang Woo-suk is charged with fraud, embezzlement and violating the country's laws on bioethics. He faces up to 13 years in prison Taken from NPR’s Key Moments in the Stem-Cell Debate

Stem Cell Timeline Aug. 23, 2006: Scientists unveil a new technique they claim could break the political deadlock over human embryonic stem cells. Researchers with the company Advanced Cell Technology say it's possible to remove a cell from an embryo without harming the embryo and then grow the cell in a lab dish. That single cell could then be used to derive embryonic stem cells. Jan. 7, 2006: Researchers at Wake Forest University and Harvard University report that stem cells drawn from amniotic fluid donated by pregnant women hold much the same promise as embryonic stem cells. They reported they were able to extract the stem cells from the fluid, which cushions babies in the womb, without harm to mother or fetus and turn their discovery into several different tissue cell types, including brain, liver and bone. Nov. 20, 2007: Two independent teams, one from Kyoto and the other from Wisconsin, simultaneously report on a method for making human embryonic stem cells without destroying a human embryo. Taken from NPR’s Key Moments in the Stem-Cell Debate

Stem Cells, Thomson, & Wisconsin James Thomson has been called “The Father of Stem Cell Research”. As a researcher at UW-Madison, he was both the first to isolate primate and then human stem cells as well as convert adult cells (from skin) into embryonic stem cells. He currently is a professor at the University of Wisconsin School of Medicine and Public Health, and is a faculty member of the Genome Center of Wisconsin where he conducts his research. His doctorates are in veterinary medicine and molecular biology. Through his efforts, Wisconsin has led the world in the creation and development of stem cell technologies. uc.wisc.edu

Adult vs. Embryonic Stem Cells One major difference between adult and embryonic stem cells is their ability to form different kinds of tissue. Embryonic stem cells can become all cell types of the body because they are pluripotent. Pluripotent: Having the ability to give rise to all of the various cell types of the body. Adult stem cells under normal conditions can only become a specific kind of tissue E.g. skin stem cells can only become more skin elements4health.com

Stem Cell Probs Embryonic stem cells can be grown relatively easily in culture. Adult stem cells are rare in mature tissues Isolating these cells from an adult tissue is challenging Methods to reproduce them in a lab has not yet been worked out. Large numbers of cells are needed for stem cell replacement therapies Adult stem cells, under current methods, would not work for this. thetech.org

Stems Cells & Transplants Scientists believe that tissues derived from embryonic and adult stem cells may differ in the likelihood of being rejected after transplantation. We don’t yet know whether tissues derived from embryonic stem cells would cause transplant rejection The first phase of clinical trial testing has only recently been approved by the FDA Adult stem cell tissue may be better for transplantations if the source of the stem cell was from the patient.

Controversy Creating embryonic stem cells has required the destruction of those embryos. For this reason, the use of federal funds to research embryonic stem cells was banned under President Bush The only exception to this was for 60 stem cell lines that were already created beforehand (many of which were at UW). This policy was overturned in 2009 by President Obama. cbsnews.com

Controversy Over? The 2007 breakthrough by Thomson’s team in Wisconsin and another team in Kyoto meant that it is possible to “reverse” the differentiation of a cell and turn it back into an embryonic stem cell. However, there is still a lot of work that has to occur before this is a viable replacement to embryonic stem cells. msnbc.msn.com

Stem Cell Possibilities The ultimate hope of regenerative medicine is to create the kinds of tissue or organs needed for transplant patients. To be useful for transplant purposes, stem cells must be reproducibly made to: Proliferate extensively and generate sufficient quantities of cells for making tissue. Differentiate into the desired cell type(s). Survive in the recipient after transplant. Integrate into the surrounding tissue after transplant. Function appropriately for the duration of the recipient’s life (without failure) Avoid harming the recipient in any way (e.g. there is a risk of stem cells spreading and becoming cancerous). Significant technical hurdles remain that will only be overcome through years of intensive research. Source: National Institute of Health