Adult Stem Cells, Homeostasis, and Regenerative Medicine

What are Adult Stem Cells? An adult stem cell is an undifferentiated (or partially-differentiated) cell found in tissues and organs They can self-renew and differentiate to become most or all of the specialized cell types within their specific tissue lineage. Adult stem cells Maintain cell populations Help you heal Play a role in aging Undifferentiated - Of, or describing a cell that has not yet acquired a special structure and function; pertaining to an immature cell or a primitive cell Self-renew - the ability to go through numerous cycles of cell division while maintaining the undifferentiated state. Differentiate - the process by which a less specialized cell becomes a more specialized cell type Specialized - Specialized cells perform specialized functions in multicellular organisms. Groups of specialized cells cooperate to form a tissue, such as a muscle.

Homeostasis The ability to regulate internal conditions, usually by a system of feedback controls Stabilize health and functioning, regardless of the outside changing conditions. One piece of homeostasis is the constant or periodic generation of new cells to replace old, damaged, and dying cells Adult stem cells fulfill this role through the process of regeneration

How Regeneration Works Adult stem cells normally remain quiescent (non-dividing) for relatively long periods of time until they are activated by signals to maintain tissues When activated they divide through a process called asymmetric cell division Through this process they are able to maintain their populations and differentiate into the desired cell types by the creation of a progenitor cell A progenitor cell, in contrast to stem cells, is already far more specific: they are pushed to differentiate into their "target" cell.

Asymmetric Cell Division Proliferates Maintains pop. Creates Progenitor Cell Progenitor cell Q: How is a stem cell different from other normal (somatic) cells? A1: A stem cell can divide over and over again. Embryonic stem cells can divide indefinitely in culture. “Adult” stem cells appear when those three distinct layers show up, but they can only divide a limited number of times in culture. A2: Both embryonic and adult stem cells have the potential to differentiate (or mature) into a range of specialized cell types. Adult stem cells are more restricted than embryonic stem cells in what they can become. Which will be more useful for research and medicine has yet to be confirmed. A3: Stem cells can migrate to where they are needed, although other non-stem cells can do this too. Q: How many cell types can embryonic stem cells differentiate into? A1: All of the 200+ mature cell types in the adult body, including all of the types of adult stem cells. Stem cell Stem cell

A progenitor cell further differentiates into CLICK A progenitor cell further differentiates into CLICK! a mature cell type, like the skin cell in green. The stem cell can divide again, CLICK! this time producing a different type of progenitor cell CLICK! which matures into yet another cell type, CLICK! like a neuron in pink. In this way, stem cells can regenerate tissues after injury and maintain healthy cells and cell numbers.

Location of Adult Stem Cells Adult stem cells and progenitor cells reside through out your body These stem cells reside in a specific area of each tissue called the “stem cell niche” This niche is a particular microenvironment that fosters the growth of resident stem cells Mutations in cells, signals they receive, and changes in the microenvironment can activate a stem cell

Types of Adult Stem Cells Hematopoietic stem cells: blood and immune system Mesenchymal stem cells: bone, cartilage, fat, muscle, tendon/ligament Neural stem cells: neurons, glial cells Epithelial stem cells: skin, linings

Hematopoietic stem cells Give rise to all the blood cell types: Myeloid (monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets, dendritic cells) Lymphoid (T-cells, B-cells, NK-cells) Found in the bone marrow from very early on in development, as well as in umbilical cord blood and placental tissue

Mesenchymal stem cells These stem cells will differentiate into: cartilage cells (chondrocytes) muscle cells (myocytes) fat cells (adipocytes) tendons, ligaments, and connective tissue (epithelial cells including osteoblasts)  These cells are located throughout the body Bone marrow, fat, and cord blood are easiest to isolate Smooth muscle cells (red) © CIRM

Neural stem cells They are located in: Subventricular zone lining the lateral ventricles, where they give rise to newly-born neurons that migrate to the olfactory bulb via the rostral migratory stream Subgranular zone, part of the dentate gyrus of the hippocampus Neural stem cells (also called Neural precursor cells) give rise to neurons, oligodendrocytes, and astrocytes Top: Section of the hippocampus, blue dots are neural stem cells Left: Mature neuron (red) © CIRM

Epithelial stem cells Give rise to epithelial cells which constitute 60 percent of the differentiated cells in the body. Responsible for covering the internal (i.e. intestinal lining) and external surfaces (i.e. skin) of the body, including the lining of vessels, glands, and other cavities. Epithelial stem cells are also found in the bulge region of the hair follicle http://www.nature.com/nature/journal/v414/n6859/images/414098ae.2.jpg Retinal pigment epithelial cells © CIRM

Adult Stem Cell Therapies Bone Marrow Transplant Although they are more difficult to obtain than embryonic stem cells, adult stem cells do have therapeutic potential which some of you might have heard about. A well-established adult stem cell therapy is a bone marrow transplant. Bone marrow transplants have been practiced for 40 years as a treatment for diseases of the blood, bone marrow, and certain types of cancer like leukemia. FIRST, a donor’s tissue type is matched with the patient’s tissue type to make sure the patient won’t reject the transplant. NEXT, bone marrow containing hematopoietic (hee-mat-oh-poetic), or blood-forming, stem cells is taken from the donor’s pelvis. THEN, right before the transplant, the recipient patient receives chemotherapy to destroy all of their malignant blood cells. FINALLY, the donor’s stem cells are filtered out and given in a transfusion to the patient, and the cells will find their way to the bone marrow and eventually repopulate the patient’s blood system. Sometimes instead of receiving stem cells from a donor, the patient can receive their own stem cells. Umbilical cord, the tissue connecting baby to mother before birth, is a rich source of hematopoietic (hee-mat-oh-poetic) stem cells. The umbilical cord is usually thrown away after a baby is born, but some people choose to “bank” the umbilical cord blood cells in case the child needs to use those stem cells later on. Hematopoietic stem cells from umbilical cord do not have the same immune-rejection issues as hematopoietic stem cells from bone marrow, which makes them ideal for therapies.

Tissue Specific Organs In November 2008, scientists in Spain carried out a trachea transplant for a woman whose windpipe had been damaged by tuberculosis. The doctors took adult stem cells and some other cells from the healthy right airway of the woman needing the trachea transplant, grafted those cells onto the stripped-down donated (cadaver) trachea, and marinated the trachea in chemicals in a lab to coax the trachea into rebuilding itself. http://newsimg.bbc.co.uk/media/images/45220000/gif/_45220227_961188b5-37a0-4aec-a13d-140e8bc0e7c7.gif

Clinical Trials Clinical trials are conducted in phases. The trials at each phase have a different purpose and help scientists answer different questions: Phase I trials: researchers test an experimental drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. Phase II trials: the experimental study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety. Phase III trials: the experimental study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely. Phase IV trials: post marketing studies delineate additional information including the drug's risks, benefits, and optimal use. A research study in human beings that follows a pre-defined protocol.

Risk vs. Benefits of Participating in a Clinical Trial The patient must stop taking other treatments before the trial There may be unpleasant, serious or even life-threatening side effects to experimental treatment. The experimental treatment may not be effective for the participant, or given a placebo The protocol may require more of their time and attention than would a non-protocol treatment, including trips to the study site, more treatments, hospital stays or complex dosage requirements. Benefit Play an active role in their own health care. Gain access to new research treatments before they are widely available. Obtain expert medical care at leading health care facilities during the trial. Help others by contributing to medical research. The patient may get better as a result of the experimental treatment. Patients who receive the placebo are usually, but not always, given access to the treatment once the trial ends

Stem Cell Tourism In what is called “stem cell tourism” patients travel to other countries with less restrictions to receive stem cell therapies. Sometimes experimental and can be dangerous There are many legitimate therapies going through national regulatory processes in these countries. December 2008 study of stem cell clinic web sites Sites claimed to treat a range of diseases that go beyond the scope of the early evidence on stem cells' efficacy Played up the benefits and talked little about risks Each treatment costs around $21,500