All Things Stem Cell

While there is great potential for using stem cells in regenerative therapies, there is still a ways to go before it can be considered a proven practice, although recent breakthroughs, and one specific trial in particular, makes it seem much closer. Recently, the first human tissue-engineered organ using stem cells was created and transplanted successfully into a patient. Other tissue regeneration efforts with stem cells have also recently made many breakthroughs, emphasizing the potential of using stem cells in future tissue transplants.

In the first reported instance of using stem cells to bioengineer a functional human organ, Paolo Macchiarini and his research group used a patient’s own stem cells to generate an airway, specifically a bronchus, and successfully grafted it into the patient to replace her damaged bronchus (See Figure 1). Macchiarini’s group bypassed the problem of immune rejection by using the patient’s own stem cells. Additionally, by combining a variety of bioengineering efforts, no synthetic parts were involved in the creation of the organ; it was made entirely of cadaveric and patient-derived tissues (Macchiarini et al., 2008; Hollander et al., 2009).

Figure 1. In order to create a patient-compatible replacement bronchus, Macchiarini’s group removed and decellularized a trachea from a cadaveric donor, grew cells removed from the patient on the trachea in a bioreactor, and then transplanted the bioengineered airway into the patient, successfully replacing their defective bronchus (Macchiarini et al., 2008).

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admin Bioengineering, Mesenchymal Stem Cells adult, clinical trials, mesenchymal, regenerative medicine

Human embryonic stem cells (hESCs) recently celebrated the 10th anniversary of their discovery, and in the decade since their isolation they have possibly received more press coverage, both over their many potential applications as well as ethical concerns, than any other type of stem cell. In the last decade, much progress has been made in better understanding these cells and their capabilities. hESCs hold much promise not only for being cellular models of human development and function, but also for use in the field of regenerative medicine. However, due to ethical and application concerns, only recently have these cells made it to clinical trials.

Figure 1: The Blastocyst. Human embryonic stem cells are isolated from early-stage embryos in the late blastocyst stage, about four or five days after fertilization. The blastocyst is a hollow sphere made of approximately 150 cells and contains three distinct areas: the trophoblast, which is the surrounding outer layer that later becomes the placenta, the blastocoel, which is a fluid-filled cavity within the blastocyst, and the inner cell mass, also known as the embryoblast, which can become the embryo proper, or fetus, and is where hESCs are isolated from.

Though human embryonic stem cells were isolated just over a decade ago, embryonic stem cells were successfully isolated from other animals before this. Nearly 30 years ago, two groups independently reported the isolation of mouse embryonic stem cells (mESCs) (Martin, 1981; Evans and Kaufman, 1981). The mESCs were isolated from early-stage mouse embryos, approximately four to six days post-fertilization (out of 21 days total for mouse gestation). At this point in development, the embryo is in the late blastocyst stage (see figure 1). It was not until the mid-1990s that this feat was accomplished with non-human primates by Dr. James Thomson’s group (Thomson et al., 1995). Only a few years later, embryonic stem cells isolated from humans, once again by Thomson’s group, in 1998 (Thomson et al., 1998).

It is important to understand where hESCs come from in order to understand the ethical arguments that surround them, as well as their enormous, innate biological potential. Like mESCs, hESCs are isolated from early-stage embryos that are, specifically, in the late blastocyst stage, about four or five days after fertilization. After the fertilized egg cell starts cell division, what is referred to as the “blastocyst” occurs once the cell has divided into a hollow sphere made up of approximately 150 cells (see figure 1). At this point, the embryo has not even yet been implanted in the uterus. The blastocyst contains three distinct areas: the trophoblast, which is the surrounding outer layer that later becomes the placenta, the blastocoel, which is a fluid-filled cavity within the blastocyst, and the inner cell mass, also known as the embryoblast, which can become the embryo proper, or fetus. Embryonic stem cells can be created from cells taken from the inner cell mass (Stem Cell Basics: What are embryonic stem cells?, 2009). Because these cells are taken from such an early stage in development, they have the ability to become cells of any tissue type (except for the whole embryo itself), making them pluripotent. The pluripotency of hESCs is probably the trait that contributes most to their enormous potential, both as models of cell function and human development and, potentially, for uses in regenerative medicine. Being pluripotent and seemingly unlimited in supply separates hESCs from adult stem cells, which are multipotent or unipotent, able to become a more select group of cell types, and more limited in their cellular lifespan.

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admin Embryonic Stem Cells clinical trials, embryonic, history, news, regenerative medicine

Often the feasibility of using stem cells for regenerative therapies is limited by two factors: obtaining a significant number of cells and doing so in a relatively noninvasive manner. Because our bodies freely shed a limited and select number of cells, many stem cell types must be obtained using a rather invasive procedure. However, around the beginning of last year two laboratories independently reported the discovery of a new type of stem cell that may overcome both obstacles; stem cells were found to reside in menstrual blood (Meng et al., 2007; Patel et al., 2008). These stem cells, termed endometrial regenerative cells (ERCs), are not only harvested in a noninvasive manner and relatively readily available in large quantities, but they potentially overcome the problem of immune rejection in many female patients as well.

The uterus is lined by a layer of cells called the endometrium. During the menstrual cycle, the endometrium cycles between thickening and being broken down if fertilization does not occur. The break down and expulsion of the endometrium is called menstruation, or menstrual bleeding, and is the source of endometrial regenerative cells (ERCs).

Researchers suspected stem cells to be present in menstrual blood because stem cells were previously found to be present in the lining of the uterus. The wall of the uterus is lined by a layer of cells called the endometrium (see figure). To create ideal conditions for the uterus to accept and nurture an embryo, the endometrium lining becomes thicker and increases the number of blood vessels and glands within it. However, if implantation does not occur, the endometrium lining is broken down and shed. Overall, the endometrium is quite a hyperproliferative tissue, continuously being broken down and rebuilt; it is an ideal tissue to investigate for the presence of stem cells. In the menstrual cycle, the shedding is known as menstruation, or menstrual bleeding; the excreted menstrual blood is made up of blood as well as cells from the endometrium layer. Researchers previously reported the presence of stem cells in the intact endometrium lining of the uterus (Cho et al., 2004; Schwab et al., 2005; Du and Taylor, 2007). Because stem cells were found in the endometrium, researchers thought it likely that stem cells could also be found in the shed endometrium in the form of menstrual blood, which can be obtained in relatively large quantities in a much less invasive manner. However, the stem cells discovered in menstrual blood, ERCs, appear to be rather different from stem cells derived from the intact endometrium.

While stem cells from the intact endometrium appear to be mesenchymal stem cells (MSCs, as discussed earlier), ERCs do not; they are distinctly different not only in their undifferentiated state, but in the cells they can differentiate into as well. Researchers categorize stem cells into certain groups based off of, among other factors, their cell morphology and the proteins they express. An established stem cell group usually expresses a distinct set of proteins. ERCs, though morphologically appearing mesenchymal, were found to express only some, but not all, proteins characteristic of MSCs. Additionally, ERCs were reported to be able to differentiate into, or become, cells from the three different germ layers (see the previous post on MSCs for more details): mesoderm (muscle, bone, fat, cartilage, and endothelial cells), ectoderm (neurons), and endoderm (liver, pancreas, and lung cells) (Meng et al., 2007; Patel et al., 2008). However, the mesenchymal stem cells from the intact endometrium cannot generate cells from all three germ layers. Overall, ERCs were determined to be functionally distinct from endometrium MSCs (Meng et al., 2007; Hida et al., 2008).

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admin Endometrial Regenerative Cells adult, clinical trials, embryonic, hematopoietic, mesenchymal, news, regenerative medicine

Recently, a patient with leukemia and human immunodeficiency virus (HIV) had apparent remission of both after stem cell transplants (Hütter et al., 2009). As discussed earlier, hematopoietic stem cells have been used in transplants to rescue patients with leukemia, but this method has not previously been as successful for treating HIV, the virus that causes acquired immunodeficiency syndrome (AIDS).

Once in the body, HIV primarily attacks the immune system, such as T cells, though some individuals have T cells that are naturally resistant to HIV infection. Over a decade ago, this resistance was found to be due to a mutation in a receptor that is normally on the cell surface of T cells, called chemokine receptor 5 (CCR5) (Liu et al., 1996). CCR5 is a chemokine receptor, meaning it normally binds and receives signals from chemokines, which are molecules cells can release and receive to cause an immune system response. CCR5 is thought to normally be involved in causing a response to infection, though its exact function is not fully understood. HIV normally interacts with CCR5 to gain entry into the target T cell, but some individuals have a mutation in the CCR5 gene, specifically a 32 base-pair deletion, that renders the resultant receptor completely nonfunctional and consequently prevents HIV from being taken into these cells (Liu et al., 1996).

The T cell membrane (shown as the purple, semicircle double line) allows entry of HIV (in pink) into the cell through multiple cell receptors anchored on the membrane, including CCR5.

admin Hematopoietic Stem Cells adult, clinical trials, gene therapy, hematopoietic, news

Promising cures for blood-related diseases, such as leukemia and lymphoma, hematopoietic stem cells (HSCs) have been heavily researched for decades. However, like many significant findings in science, their discovery was not made in search for such a cure, but stumbled upon while dealing with another serious medical issue of the time: radiation. While trying to treat people exposed to lethal doses of radiation during World War II, transplants from the spleen and bone marrow were found to rescue these victims (Ford et al., 1956). It was not until later that scientists determined that the HSCs present in these tissues were what was restoring the damaged tissues, observed by performing transplants using lethally irradiated mouse and rat models (Becker et al., 1963). HSCs in humans were further characterized and cultured in the 1980s (Morstyn et al., 1980; Sutherland et al., 1989; Sutherland et al., 1990). The formation of the National Marrow Donor Program during this time also greatly improved the availability of these cells for research. Not only have HSCs been successfully used clinically in humans since the 1950s, but to this day they are still one of the few adult stem cells to be tested for clinical uses.

It is now not only better understood how HSCs from a donor animal can save a lethally irradiated recipient animal, but how HSCs can be used in many other medical applications as well. HSCs are able to give rise to all cells in the hematopoietic system, which includes myeloid elements (i.e. red blood cells, white blood cells, platelets) and the lymphatic system (i.e. T-Cells) (Regenerative Medicine, 2006). Because radiation generally targets rapidly dividing cells, including bone marrow cells and cells in the lymphatic system, HSCs have the ability to replenish the supply of cells most damaged by radiation. While HSCs can be collected from adult bone marrow, some fetal tissues (liver, spleen, thymus), umbilical chords, and peripheral blood, in recent years there has been a great shift towards obtaining HSCs mainly from peripheral blood, using a much simpler and less controversial procedure, though achieving a large enough number of HSCs for transplants is still an obstacle to overcome (Stem Cells, 2001). HSCs are now being used to treat cancers of the hematopoietic system (leukemia and lymphomas), replenish cells lost to high-doses of chemotherapy, and fight against autoimmune diseases, in addition to other medical applications (Regenerative Medicine, 2006).

Hematopoietic stem cells give rise to two major progenitor cell lineages, myeloid and lymphoid progenitors (Regenerative Medicine, 2006).

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admin Hematopoietic Stem Cells adult, clinical trials, hematopoietic, history