All Things Stem Cell

Dr. Teisha J. Rowland, the author of “All Things Stem Cell,” recently published a book inspired by this blog. In the book Biology Bytes: Digestible Essays on Stem Cells and Modern Medicine, author Dr. Rowland discusses the history and latest scientific advancements in these fields of science, and many more. With a specific focus on issues that we increasingly encounter in the modern world around us, Dr. Rowland explores cutting-edge science through essays that can be easily digested: complex scientific concepts are broken down into key points based on the latest discoveries, technical jargon is clearly explained, and the impacts of these discoveries on our lives is explored. This book includes comprehensible explorations of a wide range of topics, including different types of stem cells and treatments they may be used in (with updated essays from “All Things Stem Cell”), the development and impact of in vitro fertilization (a technique responsible for over 1% of U.S. births today), how and why GMOs are made, the creation of vaccines to fight cancer, and fascinating food science behind delectable drinks such as beer, wine, and tea. For $4.99, you can own the book!

Additionally, Dr. Rowland recently started a general biology blog titled “Biology Bytes” (at www.biology-bytes.com). The blog has short articles posted twice a week (Tuesdays and Thursdays) on a variety of biology topics, so far ranging from melanoma in fish, toads that hatch eggs inside their skin, and the decline of the honey bees, to less technical coverage of stem cell topics. The most recent article, “Lab-Grown Meat: Triumphs and Challenges,” is on the muscle stem cells used to create the recently taste-tested stem cell “meat” patty — it is a less technical (and shorter) version of the “All Things Stem Cell” post “Cooking with Stem Cells.” Tune in to “Biology Bytes” for bi-weekly short stories on a wide array of fascinating biology topics, including more accessible explanations of stem cell biology.

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On August 5, 2013, a “lab-grown,” 5-ounce burger patty was taste tested in London, U.K. The patty had been grown from muscle stem cells that were isolated from cows. While this piece of “meat,” which was said to have tasted “close to meat,” represents significant progress in the field of making lab-grown food, the current approach needs to be improved before widespread use is feasible; the patty cost over $330,000 to make (not to mention probably significant culturing time in the lab to generate the 20,000 muscle strands used to make the patty). Luckily, there are many avenues that can be explored to optimize this technology. To understand them, it’s important to first understand the muscle stem cells themselves and how they’re cultured.

Origins of Muscle Stem Cells:
During development, the embryo has three different tissue types that, together with the germ cells, will make up the animal’s entire body. These are called the three germ layers. One of these tissue types, specifically the mesoderm, develops into skeletal muscle cells (along with other cell types, including cardiac muscle, kidney cells, red blood cells, and smooth muscle). Some stem cells that have been isolated from muscle appear to be mesenchymal stem cells. Mesenchymal stem cells (MSCs) got their name because they’re thought to primarily contain progenitors in the mesenchyme, which is a collection of cells mostly derived from mesoderm. (The majority of these cells later make up supportive structures throughout the body, such as bone, cartilage, connective tissue, muscle, adipose tissue, and the lymphatic and hematopoietic systems.) MSCs are typically multipotent, which means they can differentiate, or turn into, multiple different cell types. Specifically, MSCs are usually confirmed to be MSCs by showing that they can differentiate into three different, standard mesenchymal cell types: osteocytes (bone), chondrocytes (cartilage), and adipocytes (fat).

In muscle, there are two main groups of stem cells: satellite cells and muscle-derived stem cells (MDSCs) (Jankowski et al., 2002). Satellite cells were discovered decades ago (Mauro, 1961) and are commonly simply (and perhaps confusingly) referred to as muscle stem cells. It’s thought that these cells can regenerate damaged skeletal muscle and self-renew, but their ability to differentiate is rather limited; they can only make other types of muscle cells. (They’re basically unipotent.) MDSCs, on the other hand, are thought to be a type of multipotent mesenchymal stem cell and possibly a precursor of the satellite cells. But not only can the MDSCs differentiate into mesenchymal cell types, they have been found capable of becoming non-mesenchymal cell types as well. However, when picking the right stem cells to use for making lab-grown meat, the ability to differentiate into many different cell types is, for once, not an appealing trait.
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International Stem Cell Awareness Day is October 3, 2012, so on this day please help spread the word about the importance of stem cell research! Stem cell researchers across the world are investigating how stem cells can be used to improve our lives, from repairing and regenerating damaged or lost tissues, to developing cures for numerous devastating diseases and conditions, such as cancer, Alzheimer’s, macular degeneration, Parkinson’s, and paralyzing spinal cord injuries, and various other useful applications in between: They’re being used to help us learn more about the entire developmental process (giving us a better understanding of how to fix problems that can arise during development), the efficacies of different drugs are studied and characterized using stem cells, and their unique biological roles make them ideal for use in better understanding aging.

So please be sure to get out the word on stem cells this October 3! For more information on International Stem Cell Awareness Day (and free wallpapers and downloadable stem cell images!), visit StemCellsOfferHope.com, which is affiliated with the Sue & Bill Gross Stem Cell Research Center at the University of California, Irvine. Read on for a summary of stem cell history and recent research breakthroughs and highlights.

With all of the breaking news stories that come out on cutting-edge stem cell findings all the time, it can be easy to lose sight of the bigger picture. Yes, the stem cell family, which includes all of the varieties of stem cells that have been discovered so far, is very large, and growing larger with new children, cousins, uncles, and aunts being discovered or created all the time. But a key feature they all share is their potential to improve our lives.

Our understanding of these cells and their incredible potential for treating diseases, fight cancers, heal wounds, and, in essence, saving lives, has grown hugely since we first unknowingly used them in World War II. However, the more we learn about them the more we realize we have yet to understand. This blog has strived to explore the different stem cell types in detail, including their biology, history, potential, clinical applications, and numerous remaining questions. However, the ways in which the different types of stem cells came to be accepted into the stem cell family is itself an interesting story, and one that can help paint a useful bigger picture, and that is why this story will be the focus for this blog post to celebrate International Stem Cell Awareness Day.

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A recently published paper showed that mice with colon cancer can be “vaccinated” with human embryonic stem cells and have a significant immune response against the cancer (Li et al., 2009). This study relates to a big hurdle that needs to be overcome in order to better fight cancer: immune tolerance. The immune system usually fails to detect and attack cancerous tumors, and consequently many cancer treatments are currently being developed that stimulate the immune system to fight back (e.g. the growing field of cancer vaccines).

Cancerous tumors and embryonic tissues have been found to share many of the same antigens, which are detected by the immune system through antibodies. This group of antigens is called oncofetal antigens. Consequently, animals can be vaccinated with embryonic tissues/cells (most recently done with human embryonic stem cells) and develop an immune response against cancer.

Interestingly, this state of immune tolerance is similar to what happens during pregnancy, and, more specifically, it’s been found that the body’s response to a tumor is very similar to its response to embryonic tissues. While much recent research has not been published in this area, there is actually a long history of studies that show: (1) there is a significant number of antigens shared between tumors and embryonic tissues (called “oncofetal antigens”) and, consequently, antibodies made against tumors can also recognize embryonic tissues, and vice versa; (2) pregnancy confers some immunity against cancer (accompanied by antibody production against oncofetal antigens), not only against its occurrence but also against its growth; (3) similar to pregnancy, an immune response against cancer can be generated by vaccinating animals with embryonic tissues. These studies and the recent re-visitation will be explored below (for a more detailed review, see Brewer et al., 2009).

The first published suggestion that tumors may have an embryonic nature came in the early 1800s (Muller, 1838). Tumors were suspected to be tissues that had been triggered to become embryonic-like again, and it is now generally accepted that tumors are indeed more “embryonic” than the tissues they are derived from, due to the re-expression of embryonic-related genes. By the late 1800s, researchers understood cancer enough to realize that they must better understand normal development in order to better combat cancerous tumors and their embryonic-like cells (Brewer et al., 2009). In the 1880s, these studies shifted focus; the field of immunology was born (from research conducted by Louis Pasteur, at the University of Strasbourg, and Robert Koch, as a medical officer in Poland) and many researchers focused on creating vaccines to cure diseases. Cancer was no exception.
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A goal of regenerative medicine has been to be able to take any cell from a person’s body and turn it in to any other cell type that may be desired (such as insulin-producing beta-cells for treating diabetes, or creating neurons to treat a neurodegenerative disease). This would eliminate several donor-compatibility problems, and potentially eliminate the need for a donor (who isn’t the patient) altogether. In 2007, human induced pluripotent stem cells (iPSCs) were created and this goal seemed a bit closer (Yu et al., 2007; Takahashi et al., 2007). iPSCs are cells that can be take from adult tissue and “reprogrammed” into embryonic stem cell (ESC)-like cells. Because iPSCs are pluripotent, these cells can then differentiate into (or become) any cell type (for more information, see the All Things Stem Cell article on “Induced Pluripotent Stem Cells: A New Stem Cell Line with a Long History”).

But is it possible to get rid of the iPSC-middle man? Is it possible to take any cell in the adult body and directly reprogram it, skipping the iPSC state, into the final desired cell type? There have been several studies over the last few decades that show this is quite possible, though it still has a ways to go before it can be regularly used in the clinic.

Reprogramming of cells to a different cell type is usually done by either somatic cell nuclear transfer (SCNT) or by using transcription factors. This post will focus on work done with transcription factors (for more information on using SCNT, see the “Induced Pluripotent Stem Cells…” post). Transcription factors are expressed (or made) at different levels in different cell types, and control what genes are expressed in every cell, making sure, for example, that a liver cell remains a liver cell and does not become a neuron. A famous example of how transcription factor expression can be used to alter a cell’s identity is the creation of iPSCs, where adult cells were forced to express transcription factors normally expressed in ESCs, which made the adult cells express genes specific to ESCs, and consequently become nearly identical to ESCs.

There are many degrees of direct reprogramming that have been reported over the last few decades. Several progenitor cells, cells that appear to be committed to their fate but not yet fully differentiated, have been shown to be capable of dedifferentiating into a different cell type; this process is called transdetermination. However, in a few cases it has been shown that a fully differentiated cell can actually become a different cell type; this process is called transdifferentiation (Graf and Enver, 2009). Over the last few decades, much progress has been made in direct reprogramming with muscle, blood, the pancreas, and neurons.

Muscle

In the 1980s, the first reprogramming experiments using transcription factors took place. In 1987, a group reported using MyoD to make fibroblasts become muscle cells (Davis et al., 1987). Fibroblasts are cells important for wound healing (they secrete essential extracellular matrix proteins) and are common in connective tissues. The specific fibroblasts used were embryonic mouse fibroblasts. Because they were embryonic, this process is called transdetermination; the embryonic fibroblasts could probably differentiate more easily than adult fibroblasts (Graf and Enver, 2009). To convert the fibroblasts into muscle cells, the researchers transfected the fibroblasts with the cDNA of MyoD, forcing the cells to express MyoD (Davis et al., 1987). MyoD is normally only expressed in skeletal muscle, and it was later found to be a transcription factor involved in the differentiation of muscle cells and also a very early marker of muscle cell fate commitment.

Because of its success with the fibroblasts, MyoD was subsequently used in many other reprogramming studies to see what other cells it could make into muscle. It was found that while MyoD could indeed convert many different cell types into muscle, including fibroblasts in the dermal layer of skin, immature chondrocytes (cells in cartilage), smooth muscle, and retinal cells (Choi et al., 1990), MyoD could not turn any cell type into muscle; it was found incapable of making muscle out of hepatocytes (cells in the liver) (Schäfer et al., 1990).

Blood

In the 1990s, another key direct reprogramming factor was discovered, specifically involved in hematopoiesis. Hematopoiesis is the process by which the different types of blood cells are generated in the body (the term literally means “to make blood”). (For information on hematopoietic stem cells, see the All Things Stem Cell article “Hematopoietic Stem Cells: A Long History in Brief”). The central hematopoiesis-regulating factor discovered was the transcription factor GATA-1.

In 1995, a group reported that when GATA-1 was added to or removed from avian monocyte precursors, it could turn them into erythrocytes, megakaryocytes, and eosinophils (Kulessa et al., 1995). To understand the significance of these findings an inspection of hematopoiesis is required (see Figure). During hematopoiesis, hematopoietic stem cells (HSCs) (also called hemocytoblasts) give rise to all the different types of blood cells. Specifically, HSCs can first differentiate into either a common myeloid progenitor cell or a common lymphoid progenitor cell; either progenitor then further differentiates into specific blood cell types.

Direct Reprogramming in the Hematopoietic System. Several different transcription factors have been found that can directly reprogram one type of blood cell into another. Changing the expression levels of GATA-1 in monocytes (red) can make them differentiate into eosinophils, erythrocytes, or megakaryocytes. Making B-cells (B lymphocytes) express C/EBP transcription factors (blue) can cause them to differentiate into macrophages. Lastly, C/EBPs can also inhibit the function of the transcription factor Pax5; when Pax5 is deleted in B-cells they differentiate into T-cells (T lymphocytes), though they first dedifferentiate into a common lymphoid progenitor.

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