Stem Cell Clinic

Stem Cell Basics IV. | stemcells.nih.gov

By Somatic Stem Cells

An adult stem cell is thought to be an undifferentiated cell, found among differentiated cells in a tissue or organ. The adult stem cell can renew itself and can differentiate to yield some or all of the major specialized cell types of the tissue or organ. The primary roles of adult stem cells in a living organism are to maintain and repair the tissue in which they are found. Scientists also use the term somatic stem cell instead of adult stem cell, where somatic refers to cells of the body (not the germ cells, sperm or eggs). Unlike embryonic stem cells, which are defined by their origin (cells from the preimplantation-stage embryo), the origin of adult stem cells in some mature tissues is still under investigation.

Research on adult stem cells has generated a great deal of excitement. Scientists have found adult stem cells in many more tissues than they once thought possible. This finding has led researchers and clinicians to ask whether adult stem cells could be used for transplants. In fact, adult hematopoietic, or blood-forming, stem cells from bone marrow have been used in transplants for more than 40 years. Scientists now have evidence that stem cells exist in the brain and the heart, two locations where adult stem cells were not at firstexpected to reside. If the differentiation of adult stem cells can be controlled in the laboratory, these cells may become the basis of transplantation-based therapies.

The history of research on adult stem cells began more than 60 years ago. In the 1950s, researchers discovered that the bone marrow contains at least two kinds of stem cells. One population, called hematopoietic stem cells, forms all the types of blood cells in the body. A second population, called bone marrow stromal stem cells (also called mesenchymal stem cells, or skeletal stem cells by some), were discovered a few years later. These non-hematopoietic stem cells make up a small proportion of the stromal cell population in the bone marrow and can generate bone, cartilage, and fat cells that support the formation of blood and fibrous connective tissue.

In the 1960s, scientists who were studying rats discovered two regions of the brain that contained dividing cells that ultimately become nerve cells. Despite these reports, most scientists believed that the adult brain could not generate new nerve cells. It was not until the 1990s that scientists agreed that the adult brain does contain stem cells that are able to generate the brain's three major cell typesastrocytes and oligodendrocytes, which are non-neuronal cells, and neurons, or nerve cells.

Adult stem cells have been identified in many organs and tissues, including brain, bone marrow, peripheral blood, blood vessels, skeletal muscle, skin, teeth, heart, gut, liver, ovarian epithelium, and testis. They are thought to reside in a specific area of each tissue (called a "stem cell niche"). In many tissues, current evidence suggests that some types of stem cells are pericytes, cells that compose the outermost layer of small blood vessels. Stem cells may remain quiescent (non-dividing) for long periods of time until they are activated by a normal need for more cells to maintain tissues, or by disease or tissue injury.

Typically, there is a very small number of stem cells in each tissue and, once removed from the body, their capacity to divide is limited, making generation of large quantities of stem cells difficult. Scientists in many laboratories are trying to find better ways to grow large quantities of adult stem cells in cell culture and to manipulate them to generate specific cell types so they can be used to treat injury or disease. Some examples of potential treatments include regenerating bone using cells derived from bone marrow stroma, developing insulin-producing cells for type1 diabetes, and repairing damaged heart muscle following a heart attack with cardiac muscle cells.

Scientists often use one or more of the following methods to identify adult stem cells: (1) label the cells in a living tissue with molecular markers and then determine the specialized cell types they generate; (2) remove the cells from a living animal, label them in cell culture, and transplant them back into another animal to determine whether the cells replace (or "repopulate") their tissue of origin.

Importantly, scientists must demonstrate that a single adult stem cell can generate a line of genetically identical cells that then gives rise to all the appropriate differentiated cell types of the tissue. To confirm experimentally that a putative adult stem cell is indeed a stem cell, scientists tend to show either that the cell can give rise to these genetically identical cells in culture, and/or that a purified population of these candidate stem cells can repopulate or reform the tissue after transplant into an animal.

As indicated above, scientists have reported that adult stem cells occur in many tissues and that they enter normal differentiation pathways to form the specialized cell types of the tissue in which they reside.

Normal differentiation pathways of adult stem cells. In a living animal, adult stem cells are available to divide for a long period, when needed, and can give rise to mature cell types that have characteristic shapes and specialized structures and functions of a particular tissue. The following are examples of differentiation pathways of adult stem cells (Figure 2) that have been demonstrated in vitro or in vivo.

Figure 2. Hematopoietic and stromal stem cell differentiation. Click here for larger image. ( 2008 Terese Winslow)

Transdifferentiation. A number of experiments have reported that certain adult stem cell types can differentiate into cell types seen in organs or tissues other than those expected from the cells' predicted lineage (i.e., brain stem cells that differentiate into blood cells or blood-forming cells that differentiate into cardiac muscle cells, and so forth). This reported phenomenon is called transdifferentiation.

Although isolated instances of transdifferentiation have been observed in some vertebrate species, whether this phenomenon actually occurs in humans is under debate by the scientific community. Instead of transdifferentiation, the observed instances may involve fusion of a donor cell with a recipient cell. Another possibility is that transplanted stem cells are secreting factors that encourage the recipient's own stem cells to begin the repair process. Even when transdifferentiation has been detected, only a very small percentage of cells undergo the process.

In a variation of transdifferentiation experiments, scientists have recently demonstrated that certain adult cell types can be "reprogrammed" into other cell types in vivo using a well-controlled process of genetic modification (see Section VI for a discussion of the principles of reprogramming). This strategy may offer a way to reprogram available cells into other cell types that have been lost or damaged due to disease. For example, one recent experiment shows how pancreatic beta cells, the insulin-producing cells that are lost or damaged in diabetes, could possibly be created by reprogramming other pancreatic cells. By "re-starting" expression of three critical beta cell genes in differentiated adult pancreatic exocrine cells, researchers were able to create beta cell-like cells that can secrete insulin. The reprogrammed cells were similar to beta cells in appearance, size, and shape; expressed genes characteristic of beta cells; and were able to partially restore blood sugar regulation in mice whose own beta cells had been chemically destroyed. While not transdifferentiation by definition, this method for reprogramming adult cells may be used as a model for directly reprogramming other adult cell types.

In addition to reprogramming cells to become a specific cell type, it is now possible to reprogram adult somatic cells to become like embryonic stem cells (induced pluripotent stem cells, iPSCs) through the introduction of embryonic genes. Thus, a source of cells can be generated that are specific to the donor, thereby increasing the chance of compatibility if such cells were to be used for tissue regeneration. However, like embryonic stem cells, determination of the methods by which iPSCs can be completely and reproducibly committed to appropriate cell lineages is still under investigation.

Many important questions about adult stem cells remain to be answered. They include:

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Stem Cell Basics IV. | stemcells.nih.gov

Glossary | stemcells.nih.gov

By Somatic Stem Cells

Adult stem cellSee somatic stem cell.

AstrocyteA type of supporting (glial) cell found in the nervous system.

BlastocoelThe fluid-filled cavity inside the blastocyst, an early, preimplantation stage of the developing embryo.

BlastocystApreimplantationembryo consisting of a sphere made up of an outer layer of cells (thetrophoblast), a fluid-filled cavity (theblastocoel), and a cluster of cells on the interior (theinner cell mass).

Bone marrow stromal cellsA population of cells found in bone marrow that are different from blood cells.

Bone marrow stromal stem cells (skeletal stem cells)A multipotent subset of bone marrow stromal cells able to form bone, cartilage, stromal cells that support blood formation, fat, and fibrous tissue.

Cell-based therapiesTreatment in which stem cells are induced to differentiate into the specific cell type required to repair damaged or destroyed cells or tissues.

Cell cultureGrowth of cells in vitro in an artificial medium for research.

Cell divisionMethod by which a single cell divides to create two cells. There are two main types of cell division depending on what happens to the chromosomes: mitosis and meiosis.

ChromosomeA structure consisting of DNA and regulatory proteins found in the nucleus of the cell. The DNA in the nucleus is usually divided up among several chromosomes.The number of chromosomes in the nucleus varies depending on the species of the organism. Humans have 46 chromosomes.

Clone (v) To generate identical copies of a region of a DNA molecule or to generate genetically identical copies of a cell, or organism; (n) The identical molecule, cell, or organism that results from the cloning process.

CloningSee Clone.

Cord blood stem cellsSee Umbilical cord blood stem cells.

Culture mediumThe liquid that covers cells in a culture dish and contains nutrients to nourish and support the cells. Culture medium may also include growth factors added to produce desired changes in the cells.

DifferentiationThe process whereby an unspecialized embryonic cell acquires the features of a specialized cell such as a heart, liver, or muscle cell. Differentiation is controlled by the interaction of a cell's genes with the physical and chemical conditions outside the cell, usually through signaling pathways involving proteins embedded in the cell surface.

Directed differentiationThe manipulation of stem cell culture conditions to induce differentiation into a particular cell type.

DNADeoxyribonucleic acid, a chemical found primarily in the nucleus of cells. DNA carries the instructions or blueprint for making all the structures and materials the body needs to function. DNA consists of both genes and non-gene DNA in between the genes.

EctodermThe outermost germ layer of cells derived from the inner cell mass of the blastocyst; gives rise to the nervous system, sensory organs, skin, and related structures.

EmbryoIn humans, the developing organism from the time of fertilization until the end of the eighth week of gestation, when it is called a fetus.

Embryoid bodiesRounded collections of cells that arise when embryonic stem cells are cultured in suspension. Embryoid bodies contain cell types derived from all threegerm layers.

Embryonic germ cellsPluripotent stem cells that are derived from early germ cells (those that would become sperm and eggs). Embryonic germ cells are thought to have properties similar to embryonic stem cells.

Embryonic stem cellsPrimitive (undifferentiated) cells that are derived from preimplantation-stageembryos, are capable of dividing without differentiating for a prolonged period in culture, and are known to develop into cells and tissues of the three primary germ layers.

Embryonic stem cell lineEmbryonic stem cells, which have been cultured under in vitro conditions that allow proliferation without differentiation for months to years.

EndodermThe innermost layer of the cells derived from the inner cell mass of the blastocyst; it gives rise to lungs, other respiratory structures, and digestive organs, or generally "the gut."

EnucleatedHaving had its nucleus removed.

EpigeneticThe process by which regulatory proteins can turn genes on or off in a way that can be passed on during cell division.

Feeder layerCells used in co-culture to maintain pluripotent stem cells. For human embryonic stem cell culture, typical feeder layers include mouse embryonic fibroblasts (MEFs) or human embryonic fibroblasts that have been treated to prevent them from dividing.

FertilizationThe joining of the male gamete (sperm) and the female gamete (egg).

FetusIn humans, the developing human from approximately eight weeks after conception until the time of its birth.

GameteAn egg (in the female) or sperm (in the male) cell. See also Somatic cell.

GastrulationThe process in which cells proliferate and migrate within the embryo to transform the inner cell mass of the blastocyst stage into an embryo containing all three primary germ layers.

GeneA functional unit of heredity that is a segment of DNA found on chromosomes in the nucleus of a cell. Genes direct the formation of an enzyme or other protein.

Germ layersAfter the blastocyst stage of embryonic development, the inner cell mass of the blastocyst goes through gastrulation, a period when the inner cell mass becomes organized into three distinct cell layers, called germ layers. The three layers are the ectoderm, the mesoderm, and the endoderm.

Hematopoietic stem cellA stem cell that gives rise to all red and white blood cells and platelets.

Human embryonic stem cell (hESC)A type of pluripotent stem cell derived from early stage human embryos, up to and including the blastocyststage. hESCs are capable of dividing without differentiating for a prolonged period in culture and are known to develop into cells and tissues of the three primary germ layers.

Induced pluripotent stem cell (iPSC)A type of pluripotent stem cell, similar to an embryonic stem cell, formed by the introduction of certain embryonic genes into a somatic cell.

In vitroLatin for "in glass;" in a laboratory dish or test tube; an artificial environment.

In vitro fertilizationA technique that unites the egg and sperm in a laboratory instead of inside the female body.

Inner cell mass (ICM)The cluster of cells inside the blastocyst. These cells give rise to the embryo and ultimately the fetus. The ICM may be used to generate embryonic stem cells.

Long-term self-renewalThe ability of stem cells to replicate themselves by dividing into the same non-specialized cell type over long periods (many months to years) depending on the specific type of stem cell.

MeiosisThe type of cell division a diploid germ cell undergoes to produce gametes (sperm or eggs) that will carry half the normal chromosome number. This is to ensure that when fertilization occurs, the fertilized egg will carry the normal number of chromosomes rather than causing aneuploidy (an abnormal number of chromosomes).

Mesenchymal stem cellsA term that is currently used to define non-blood adult stem cells from a variety of tissues, although it is not clear that mesenchymal stem cells from different tissues are the same.

MesodermMiddle layer of a group of cells derived from the inner cell mass of the blastocyst; it gives rise to bone, muscle, connective tissue, kidneys, and related structures.

MicroenvironmentThe molecules and compounds such as nutrients and growth factors in the fluid surrounding a cell in an organism or in the laboratory, which play an important role in determining the characteristics of the cell.

MitosisThe type of cell division that allows a population of cells to increase its numbers or to maintain its numbers. The number of chromosomes in each daughter cell remains the same in this type of cell division.

MultipotentHaving the ability to develop into more than one cell type of the body. See also pluripotent and totipotent.

Neural stem cellA stem cell found in adult neural tissue that can give rise to neurons and glial (supporting) cells. Examples of glial cells include astrocytes and oligodendrocytes.

NeuronsNerve cells, the principal functional units of the nervous system. A neuron consists of a cell body and its processesan axon and one or more dendrites. Neurons transmit information to other neurons or cells by releasing neurotransmitters at synapses.

OligodendrocyteA supporting cell that provides insulation to nerve cells by forming a myelin sheath (a fatty layer) around axons.

ParthenogenesisThe artificial activation of an egg in the absence of a sperm; the egg begins to divide as if it has been fertilized.

PassageIn cell culture, the process in which cells are disassociated, washed, and seeded into new culture vessels after a round of cell growth and proliferation. The number of passages a line of cultured cells has gone through is an indication of its age and expected stability.

PluripotentThe state of a single cell that is capable of differentiating into all tissues of an organism, but not alone capable of sustaining full organismal development.

Scientists demonstrate pluripotency by providing evidence of stable developmental potential, even after prolonged culture, to form derivatives of all three embryonic germ layers from the progeny of a single cell and to generate a teratoma after injection into an immunosuppressed mouse.

Polar bodyA polar body is a structure produced when an early egg cell, or oogonium, undergoes meiosis. In the first meiosis, the oogonium divides its chromosomes evenly between the two cells but divides its cytoplasm unequally. One cell retains most of the cytoplasm, while the other gets almost none, leaving it very small. This smaller cell is called the first polar body. The first polar body usually degenerates. The ovum, or larger cell, then divides again, producing a second polar body with half the amount of chromosomes but almost no cytoplasm. The second polar body splits off and remains adjacent to the large cell, or oocyte, until it (the second polar body) degenerates. Only one large functional oocyte, or egg, is produced at the end of meiosis.

PreimplantationWith regard to an embryo, preimplantation means that the embryo has not yet implanted in the wall of the uterus. Human embryonic stem cells are derived from preimplantation-stage embryos fertilized outside a woman's body (in vitro).

ProliferationExpansion of the number of cells by the continuous division of single cells into two identical daughter cells.

Regenerative medicineA field of medicine devoted to treatments in which stem cells are induced to differentiate into the specific cell type required to repair damaged or destroyed cell populations or tissues. (See also cell-based therapies).

Reproductive cloningThe process of using somatic cell nuclear transfer (SCNT) to produce a normal, full grown organism (e.g., animal) genetically identical to the organism (animal) that donated the somatic cell nucleus. In mammals, this would require implanting the resulting embryo in a uterus where it would undergo normal development to become a live independent being. The firstmammal to be created by reproductive cloning was Dolly the sheep, born at the Roslin Institute in Scotland in 1996. See also Somatic cell nuclear transfer (SCNT).

SignalsInternal and external factors that control changes in cell structure and function. They can be chemical or physical in nature.

Somatic cellAny body cell other than gametes (egg or sperm); sometimes referred to as "adult" cells. See also Gamete.

Somatic cell nuclear transfer (SCNT)A technique that combines an enucleated egg and the nucleus of a somatic cell to make an embryo. SCNT can be used for therapeutic or reproductive purposes, but the initial stage that combines an enucleated egg and a somatic cell nucleus is the same. See also therapeutic cloning and reproductive cloning.

Somatic (adult) stem cellA relatively rare undifferentiated cell found in many organs and differentiated tissues 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. This is an active area of investigation.

Stem cellsCells with the ability to divide for indefinite periods in culture and to give rise to specialized cells.

Stromal cellsConnective tissue cells found in virtually every organ. In bone marrow, stromal cells support blood formation.

SubculturingTransferring cultured cells, with or without dilution, from one culture vessel to another.

Surface markersProteins on the outside surface of a cell that are unique to certain cell types and that can be visualized using antibodies or other detection methods.

TeratomaA multi-layered benign tumor that grows from pluripotent cells injected into mice with a dysfunctional immune system. Scientists test whether they have established a human embryonic stem cell (hESC) line by injecting putative stem cells into such mice and verifying that the resulting teratomas contain cells derived from all three embryonic germ layers.

Therapeutic cloningThe process of using somatic cell nuclear transfer (SCNT) to produce cells that exactly match a patient. By combining a patient's somatic cell nucleus and an enucleated egg, a scientist may harvest embryonic stem cells from the resulting embryo that can be used to generate tissues that match a patient's body. This means the tissues created are unlikely to be rejected by the patient's immune system. See also Somatic cell nuclear transfer (SCNT).

TotipotentThe state of a cell that is capable of giving rise to all types of differentiated cells found in an organism, as well as the supporting extra-embryonic structures of the placenta. A single totipotent cell could, by division in utero, reproduce the whole organism. (See also Pluripotent and Multipotent).

TransdifferentiationThe process by which stem cells from one tissue differentiate into cells of another tissue.

TrophoblastThe outer cell layer of the blastocyst. It is responsible for implantation and develops into the extraembryonic tissues, including the placenta, and controls the exchange of oxygen and metabolites between mother and embryo.

Umbilical cord blood stem cellsStem cells collected from the umbilical cord at birth that can produce all of the blood cells in the body. Cord blood is currently used to treat patients who have undergone chemotherapy to destroy their bone marrow due to cancer or other blood-related disorders.

UndifferentiatedA cell that has not yet developed into a specialized cell type.

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Glossary | stemcells.nih.gov

Stem Cell Basics III. | stemcells.nih.gov

By Embryonic Stem Cells

Embryonic stem cells, as their name suggests, are derived from embryos. Most embryonic stem cells are derived from embryos that develop from eggs that have been fertilized in vitroin an in vitro fertilization clinicand then donated for research purposes with informed consent of the donors. They are not derived from eggs fertilized in a woman's body.

Growing cells in the laboratory is known as cell culture. Human embryonic stem cells (hESCs) aregenerated by transferringcells from a preimplantation-stage embryointo a plastic laboratory culture dish that contains a nutrient broth known as culture medium. The cells divide and spread over the surface of the dish. In the original protocol, the inner surface of the culture dish was coated with mouse embryonic skin cellsspecially treated so they will not divide. This coating layer of cells is called a feeder layer. The mouse cells in the bottom of the culture dish provide the cells a sticky surface to which they can attach. Also, the feeder cells release nutrients into the culture medium. Researchers have nowdevised ways to grow embryonic stem cells without mouse feeder cells. This is a significant scientific advance because of the risk that viruses or other macromolecules in the mouse cells may be transmitted to the human cells.

The process of generating an embryonic stem cell line is somewhat inefficient, so lines are not produced each time cells from the preimplantation-stage embryo are placed into a culture dish. However, if the plated cells survive, divide and multiply enough to crowd the dish, they are removed gently and plated into several fresh culture dishes. The process of re-plating or subculturing the cells is repeated many times and for many months. Each cycle of subculturing the cells is referred to as a passage. Once the cell line is established, the original cells yield millions of embryonic stem cells. Embryonic stem cells that have proliferated in cell culture for six or more months without differentiating, are pluripotent, and appear genetically normal are referred to as an embryonic stem cell line. At any stage in the process, batches of cells can be frozen and shipped to other laboratories for further culture and experimentation.

At various points during the process of generating embryonic stem cell lines, scientists test the cells to see whether they exhibit the fundamental properties that make them embryonic stem cells. This process is called characterization.

Scientists who study human embryonic stem cells have not yet agreed on a standard battery of tests that measure the cells' fundamental properties. However, laboratories that grow human embryonic stem cell lines use several kinds of tests, including:

As long as the embryonic stem cells in culture are grown under appropriate conditions, they can remain undifferentiated (unspecialized). But if cells are allowed to clump together to form embryoid bodies, they begin to differentiate spontaneously. They can form muscle cells, nerve cells, and many other cell types. Although spontaneous differentiation is a good indication that a culture of embryonic stem cells is healthy, the process is uncontrolled and therefore an inefficient strategy to produce cultures of specific cell types.

So, to generate cultures of specific types of differentiated cellsheart muscle cells, blood cells, or nerve cells, for examplescientists try to control the differentiation of embryonic stem cells. They change the chemical composition of the culture medium, alter the surface of the culture dish, or modify the cells by inserting specific genes. Through years of experimentation, scientists have established some basic protocols or "recipes" for the directed differentiation of embryonic stem cells into some specific cell types (Figure 1). (For additional examples of directed differentiation of embryonic stem cells, refer to the 2006 NIH stem cell report.)

Figure 1. Directed differentiation of mouse embryonic stem cells. Click here for larger image. ( 2008 Terese Winslow)

If scientists can reliably direct the differentiation of embryonic stem cells into specific cell types, they may be able to use the resulting, differentiated cells to treat certain diseases in the future. Diseases that might be treated by transplanting cells generated from human embryonic stem cells include diabetes, traumatic spinal cord injury, Duchenne's muscular dystrophy, heart disease, and vision and hearing loss.

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By Embryonic Stem Cells

Stem cells have the remarkable potential to develop into many different cell types in the body during early life and growth. In addition, in many tissues they serve as a sort of internal repair system, dividing essentially without limit to replenish other cells as long as the person or animal is still alive. When a stem cell divides, each new cell has the potential either to remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell.

Stem cells are distinguished from other cell types by two important characteristics. First, they are unspecialized cells capable of renewing themselves through cell division, sometimes after long periods of inactivity. Second, under certain physiologic or experimental conditions, they can be induced to become tissue- or organ-specific cells with special functions. 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.

Until recently, scientists primarily worked with two kinds of stem cells from animals and humans: embryonic stem cells and non-embryonic "somatic" or "adult" stem cells. The functions and characteristics of these cells will be explained in this document. Scientists discovered ways to derive embryonic stem cells from early mouse embryos more than 30 years ago, in 1981. The detailed study of the biology of mouse stem cells led to the discovery, in 1998, of a method to derive stem cells from human embryos and grow the cells in the laboratory. These cells are called human embryonic stem cells. The embryos used in these studies were created for reproductive purposes through in vitro fertilization procedures. When they were no longer needed for that purpose, they were donated for research with the informed consent of the donor. In 2006, researchers made another breakthrough by identifying conditions that would allow some specialized adult cells to be "reprogrammed" genetically to assume a stem cell-like state. This new type of stem cell, called induced pluripotent stem cells (iPSCs), will be discussed in a later section of this document.

Stem cells are important for living organisms for many reasons. In the 3- to 5-day-old embryo, called a blastocyst, the inner cells give rise to the entire body of the organism, including all of the many specialized cell types and organs such as the heart, lungs, skin, sperm, eggs and other tissues. In some adult tissues, such as bone marrow, muscle, and brain, discrete populations of adult stem cells generate replacements for cells that are lost through normal wear and tear, injury, or disease.

Given their unique regenerative abilities, stem cells offer new potentials 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, which is also referred to as regenerative or reparative medicine.

Laboratory studies of stem cells enable scientists to learn about the cells essential properties and what makes them different from specialized cell types. Scientists are already using stem cells in the laboratory to screen new drugs and to develop model systems to study normal growth and identify the causes of birth defects.

Research on stem cells continues to advance knowledge about how an organism develops from a single cell and how healthy cells replace damaged cells in adult organisms. Stem cell research is one of the most fascinating areas of contemporary biology, but, as with many expanding fields of scientific inquiry, research on stem cells raises scientific questions as rapidly as it generates new discoveries.

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Stem-cell clinics face new scrutiny from federal …

By Stem Cell Clinic

BEVERLY HILLS, Calif. In a corner of Mark Bermans cosmetic-surgery suite is a box labeled the Time Machine that is the heart of his stem-cell operation.

In mini-liposuction procedures, Berman extracts fat tissue from patients and puts it into the Time Machine box, where a centrifuge separates stem cells from fat. The cells are then injected back into the patients to supposedly treat a variety of health problems, such as arthritic knees, heart disease, amyotrophic lateral sclerosis and even autism.

Berman, 63, is the co-founder of the biggest network of commercial stem-cell clinics in the United States. His therapies dont have the Food and Drug Administrations stamp of approval, but he said he doesnt need it.

If stem cells didnt work, we would go back to our day jobs, Berman said. Its a disruptive technology. We are the black swan.

Cosmetic surgeon Mark Berman explains how he started working with other surgeons to use stem cells taken from patients liposuction procedures to treat their other conditions. (Youtube/Cell Surgical Network)

But the disruptive technology might itself face disruption. The FDA, which has taken a mostly hands-off approach toward the rapidly proliferating stem-cell clinics, is signaling that some of the treatments should be regulated as drugs are, which would require advance approval. That would entail a lengthy process, with extensive safety and effectiveness data, at a potential cost of millions of dollars.

The issue has ignited a fierce debate among physicians, patients, scientists and politicians about whether the agency should crack down on therapies that critics deride as snake oil but that some patients swear by. And it is fueling a broader, longer-term debate over how cellular therapies should be regulated.

On Monday, the FDA opened two days of hearings on draft guidelines intended to clarify the agencys views on stem-cell treatments. The guidelines, which deal with decade-old regulations, have set off an uproar in parts of the stem-cell world because they could jeopardize many of the clinics operations.

Thats fine with some leading scientists who say the clinics are peddling potentially dangerous procedures that take advantage of desperate patients.

Hucksters are hijacking the publics enthusiasm for stem cells, said Luis Garza, a dermatologist at the Johns Hopkins School of Medicine whose lab is investigating how skin stem cells might improve care for amputees. Ninety-nine-point-nine percent of the stuff you hear about is bogus.

Paul Knoepfler, a stem-cell researcher at the University of California at Davis, said regulators for too long have remained on the sidelines while patients are charged thousands of dollars for unapproved treatments and exposed to potential risks. Im worried that these are essentially experiments, he said.

But patients who say they have benefited from clinic treatments are urging the government not to clamp down. People have the right to decide what happens in terms of the tissues and cells from their own bodies, said Doug Oliver, 54, a Nashville resident who has a rare form of macular degeneration that left him legally blind. After treatments at a Florida stem-cell clinic, he said, his vision improved significantly and now he can drive.

Stem-cell therapies, like other treatments, generally must be tested in clinical trials and approved by the FDA before being marketed to patients. But such clearance is not required if the stem cells are not altered much, are used in a function similar to their original role in the body, arent combined with another article, and dont have a systemic effect on the body. But the FDAs attempts to clarify the details have been fraught with disagreement.

Knoepfler noted, for example, that many clinics derive stem cells from fat, which the FDA views essentially as a cushioning material. Using those cells for injured knees or shoulders or diseases like Alzheimers, he said, means they are not being used for their original cushioning function.

Berman said that the versatility of stem cells means one of their basic functions is to repair damage throughout the body. In any case, he and other clinicians say, they arent subject to FDA regulation because they are practicing medicine, which the agency doesnt oversee.

Orthopedic treatments are the most commonly marketed procedures. Mayo Friedlis of the National Spine and Pain Centers, a network of pain clinics, said at the FDA hearing that stem cells derived from bone marrow are as effective as surgery for musculoskeletal disorders. But Knoepfler and other critics said there isnt enough published data to support such claims.

As the debate rages about clinics, some Republican senators, led by Mark Kirk of Illinois, want to revamp parts of the FDA approval process to expedite stem-cell therapies. But the outlook is uncertain, given the compressed congressional calendar and opposition from Democrats and some industry and patient groups.

Scientists say that stem cells remarkable ability to develop into many kinds of cells means that someday they might be used to repair diseased or damaged cells or replace entire organs. Promising developments are occurring in several areas. Stanford researchers said this year that they were stunned by the way stem cells injected directly into the brains of a small group of stroke patients had restored mobility in some patients.

Nevertheless, research for most therapies remains at an early stage, and the FDA has approved only a few stem-cell therapies, mostly for blood disorders.

Five years ago, only a few dozen stem-cell clinics existed in the United States, and most Americans seeking treatment went abroad. Now, according to a recent study co-written by Knoepfler, there are 570 clinics many in California, Florida and Texas marketing directly to consumers. Beverly Hills has 18 clinics, more than any other city. Most of the clinics use adult stem cells, not the embryonic ones that were at the center of controversy years ago because their extraction destroyed the embryos.

Berman, who spent most of his career working as a cosmetic surgeon, started providing treatments in 2010. Two years later, he co-founded the Cell Surgical Network, a stem-cell clinic business with about 80 affiliates.

Typically, Berman said, he charges patients $8,900 for a treatment, although he sometimes offers discounts or free care for patients who cannot afford his fee. He said he doesnt make claims to his patients that the treatments will work.

John Putnam, a 52-year-old Santa Monica resident, said he went to Berman four years ago, after his doctor said he needed surgery to repair sports-related injuries in both of his shoulders. At first, the stem-cell treatment didnt seem to make a difference, but after five months, he said, I had zero issues on either shoulder, and to this day my shoulders are in great shape.

Critics said that pain is very responsive to the placebo effect and that some ailments improve on their own.

Berman said his network has treated about 5,000 patients, including him and his wife, and that the only side effects have involved occasional soreness at the injection site and bruising around the abdomen because of liposuction. He said that in his experience, 85 percent of the orthopedic patients get better, and that he has seen improvement in some patients with Parkinsons disease and autism, but not in the dozen or so patients he has treated for amyotrophic lateral sclerosis (ALS).

Knoepfler brushes off such assertions and focuses on safety. He noted that two patients died after being treated at a Florida clinic. There also have been reports of patients being blinded by treatments for eye problems. And the FDA warns that stem cells can migrate to the wrong site or turn into tumors.

The clinics fate depends partly on whether the FDA sticks to the tough stance outlined in the draft guidelines. But even if it does, it is not clear that the agency will have the resources to enforce the rules, some experts said.

In the absence of strong oversight, scientists and others are worried that patients may be swayed by personal testimonials. I think we have to be careful about anecdotes, said Timothy Caulfield, a University of Alberta law professor who has followed the issue for years. We need good, controlled studies.

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What is PRP therapy? | OrthoNC

By Platelet Rich Plasma Injections

PRPisPlatelet-Rich Plasmatherapy. Although an emerging technology and technique in sports medicine, it has been used since the mid-1990s in dental and oral surgery and to aid in soft tissue recovery following plastic surgery.

RP treatment recently gained widespread recognition in the sports world when Hines Ward and Troy Polamalu of the Pittsburgh Steelers received PRP therapy prior to winning Super Bowl XLIII. Other high profile athletes include Tiger Woods who received four treatments following knee surgery and pitchers Takashi Saito and Bartolo Colon -- both recent examples of PRP success in Major League Baseball.

PRP therapy, which takes approximately twenty minutes to complete, begins with collection of 30 milliliters of the patients blood. The blood sample is placed in a centrifuge to separate the platelet-rich plasma from the other components of whole blood. Doctors then inject the concentrated platelets into the site of the injury often using ultrasound guidance for accuracy. Platelets function as a natural reservoir for growth factors that are essential to repair injured tissues. The growth factors that the platelets secrete stimulate tissue recovery by increasing collagen production, enhancing tendon stem cell proliferation, and tenocyte-related gene and protein expression. These growth factors also stimulate blood flow and cause cartilage to become more firm and resilient. PRP activates tenocytes to proliferate quickly and produce collagen to repair injured tendons, ligaments, cartilage, and muscles.

You will feel a notable increase in pain in the days immediately following the injection. Pain intensity becomes less each day as functional mobility and general functional ability increase along with endurance and strength. You will notice gradual improvement 2-6 weeks after PRP therapy. Some patients report ongoing improvement 6-9 months after PRP therapy is administered. In some studies, Ultrasound and MRI images have shown definitive tissue repair has occurred after PRP therapy, supporting the proof of the healing process. By treating injured tissues before the damage progresses, surgical intervention may be avoided.

Injuries treated with PRP therapy include: rotator cuff, quadriceps, hamstring, Achilles tendon injuries and tennis elbow. Essentially any tendon or ligament injury except complete tears may be treated successfully with PRP. PRP therapy is exactly the treatment needed to reduce the downtime of the athlete while also reducing the chance for re-injury or perhaps the risk of a more serious injury that will result in surgical intervention or permanent disability.

Not necessarily. While many chronic conditions may respond to PRP therapy, obviating the need for a surgical procedure, it is impossible to predict which will respond and which will fail to do so. A chronic, incompletely healed condition is characterized by excessive scar tissue within the tendon/ligament. This may lead to impaired joint function or leave the tendon or ligament susceptible to re-injury or complete disruption. This inferior, or in some cases, aborted, healing process is due to poor blood supply to the injury site. Most tendons have a poor blood supply and often are the site of microscopic tears or chronic scarring. The body naturally has a difficult time healing these structures. PRP is thought to initiate a response that makes the chronic condition appear to be a new injury, and thus, provoke a new/renewed healing response. This new healing response is then augmented by the super-concentrated healing factors contained within the PRP. Therefore, with PRP therapy in combination with appropriate reconditioning, we may improve the chance of healing and diminish the opportunity for escalation of the injury. A positive result may lead to a decrease need for surgical intervention.

Unfortunately, there is no randomized, prospective, double-blind clinical trial that documents the efficacy of PRP treatment. For this reason, most insurance companies will not support (read: pay for or "cover") PRP treatment. Moreover a standard treatment regimen does not yet exist (i.e. Number of injections required, spacing between injections given in series, rehabilitation protocol during and after a series, etc); however, PRP is being used with regularity at the highest levels of sport and in the most highly compensated athletes in the world today. Claims of successful treatment are purely anecdotal; case reports abound of successful PRP treatment of almost any malady. Conditions that can be treated successfully with PRP therapy include the shoulder involving: rotator cuff tendinitis, impingement, bursitis, and bicipital tendinitis; In the wrist and hand involving: DeQuervains tenosynovitis, tendinitis, ligament tears; In the elbow involving: tennis elbow and golfers elbow; the hip involving iliotibial band tendinitis (ITB Syndrome), ilio-psoas tendinitis and bursitis, greater trochanteric bursitis, sacroiliac joint dysfunction; the knee involving: patellar tendinitis, partially torn or strained major knee ligaments (LCL/MCL); the ankle and foot involving: Achilles tendinitis, peroneal tendinitis, recurrent ankle sprains, and other foot or ankle tendinitis; neck and back involving: facet joint arthritis, rib problems. I believe PRP treatment is best reserved for incomplete, chronic degeneration and tears of extra-articular ligaments and tendons. I also believe that ultrasound guidance is essential to accuracy of placement and enhancing efficacy of the injection. More research is needed to determine the best use and protocol for successful application of this, admittedly, emerging technique.

Orthopaedic Specialists of North Carolina believes that implementing PRP therapy as a viable procedure may: decrease the progression of more serious injuries, decrease the overall time for healing, and ultimately decrease the overall need for surgical intervention. This promising adjunctive form of therapy holds the potential of healing previously problematic chronic injuries, provide a treatment option for debilitating injuries previously deemed untreatable, and serve as an alternative to surgical intervention.

Written by Dr. Mark W. Galland, Orthopaedic Surgery and Sports Medicine

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What is PRP therapy? | OrthoNC

Tampa Stem Cell Therapy | PRP | Knee | Joint Replacement …

By Stem Cell Doctors

Featured in the News Across the Nation: Dr. Dennis Lox, an Expert in Sports & Regenerative Medicine, Discusses Knee Stem Cell Therapy, Hip Stem Cell Therapyand Ankle Stem Cell Therapy.

Since 1990, Dennis M. Lox, M.D. has been helping patients increase their quality of life by reducing their pain. He emphasizes non-surgical treatments and appropriate use of medications, if needed.

Many patients are turning to stem cell therapy as a means of nonsurgical joint pain relief when their mobility and quality of life are severely affected by conditions like osteoarthritis, torn tendons, and injured ligaments. Dennis M. Lox, M.D. specializes in this progressive, innovative treatment that may be able to help you return to an active, fulfilling life.

Each week, Dr. Dennis Lox receives inquiries from aroundthe worldregarding stem cell therapy.

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Stem cell therapy for joint injuries and osteoarthritis is suited for many individuals, fromprofessional athletes to active seniors. Adult mesenchymal stem cells, not embryonic stem cells, are used in this procedure, which is performed right in the comfort of Dr. Loxs state-of-the-art clinic. The cells are simply extracted from the patients own body (typically from bone marrow or adipose/ fat tissue), processed in our office, and injected directly into the site of injury. Conditions that can be addressed with stem cell treatment include osteoarthritis, degenerative disc disease, knee joint issues (such as meniscus tears), shoulder damage (such as rotator cuff injuries), hip problems (such as labral tears), and tendonitis, among others. For many patients, a stem cell procedure in the knee, hip, shoulder, or another area of the body relieves pain, increases mobility, and may be able to delay or eliminate the need for more aggressive treatments like joint replacement surgery.

If you have questions about adult stem cell therapy for joint injuries and arthritis, how the procedure is performed, and how the stem cells work to repair injured joints and tissues, Dr. Lox would be happy to educate you about the entire process.

If you are searching for effective, nonsurgical joint replacement alternatives, regenerative therapies like stem cell treatments and PRP therapy may be the ideal solution. At Florida Spine and Sports Medicine, we focus on helping patients return to mobile, independent lives without the need for the risks and downtime associated with highly invasive surgery.PRP Therapy, Stem Cell Treatments & Other Joint Replacement Alternatives for Patients in Tampa, Clearwater, New Port Richey & throughout the U.S.A. and the world.

PRP (platelet rich plasma) therapy can be used alone, or adult stem cell therapy is often used in conjunction with PRP as a means of promoting healing in degenerated or injured joints, cartilage, muscles, and tendons. From knee pain to spine pain, there are a wide range of conditions that may respond to these forms of regenerative medicine. Some of the most common issues that Dr. Lox treats at Florida Spine and Sports Medicine include knee arthritis, meniscal tears, S/I joint pain, hip conditions, shoulder pain, and ankle pain, among others.

If you live in Clearwater, St. Petersburg, New Port Richey, Tampa, or anywhere else in the nation and would like to schedule a consultation to discuss PRP therapy, stem cell therapy, or other alternatives to joint surgery with Dr. Lox, please contact Florida Spine and Sports Medicine today.

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Adult Stem Cells: The Best Kept Secret In Medicine …

By Adult Stem Cells

Stem cell therapies and their lifesaving results are arguably the best kept medical secret. Stem cells are currently being used in several thousand FDA-approved clinical trials, are treating tens of thousands of patients every year, and cumulatively over 1.5 million people have been treated to date. Yet these numbers, and the lifesaving results from stem cells for dozens of conditions, are unknown to most. Why the information blackout? Perhaps for lack of an adjective.

You see, those heartening numbers are all due to adult stem cells. Long ignored by the media and disparaged even by many in the scientific community, adult stem cells those not dependent on the destruction of embryos are the true gold standard for stem cells, especially when it comes to treating patients.

A recent New York Times piece provides a perfect example of the disinformation campaign. Early on, the author discusses the theoretical nature of stem cell treatments and bemoans the fact that progress is slow, almost all the research is still in mice or petri dishes, and The very few clinical trials that have begun are still in the earliest phase.

Whether through ignorance or bias, the sole focus is clearly on embryonic stem cells. Such writing, however, serves to confuse, not illuminate, the facts about stem cells and therapies.

Contrary to the blinkered portrayal of stem cells in the article, there are in fact almost 3,500 ongoing or completed clinical trials using adult stem cells, listed in the NIH/FDA-approved database. Moreover, large numbers of patients have been treated with adult stem cells. In 2012 there were almost 70,000 patients treated around the globe in that year alone, and almost 20,000 patients treated in just the U.S. in 2014. Cumulatively, its been documented that as of December 2012, there had already been over one million adult stem cell transplants. This means that now, over 1.5 million patients have had their lives saved and health improved by adult stem cell transplants.

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Our focus is indeed on adult stem cells both because they are efficacious for patients, as well as because adult stem cells are derived without the destruction of the stem cell donor, unlike embryonic stem cells and fetal stem cells. Both positions are based on the facts of biology.

The New York Times Kolata criticizes various stem cell clinics within the U.S., primarily via a paper by two long-time proponents of embryonic stem cells (though this is not disclosed in the article or in the paper), but paints a broad-brush across clinics operating legally and ethically as well as the shady operators. It then juxtaposes the critique of U.S. stem cell clinics with the tragic story of a patient who traveled to three different overseas clinics to receive stem cell injections and developed a growing mass of cells on his spine from at least one of the injections.

The implied warning is that all U.S. adult stem cell clinics are using similar methods, and, by extension, their patients may experience similar problems. Indeed, many clinics are offshore to avoid FDA rules, but yet again the article drops adjectives and sows confusion. The New England Journal of Medicine source on the case notes that the patient supposedly received proliferating cells including embryonic and fetal stem cells.

Certainly all clinics should operate within appropriate ethical and legal boundaries and patients should receive all information, including published background and whether the cells being used are adult, fetal, or embryonic; this is simply a matter of getting full informed consent. But fearmongering and misinformation help neither the patients nor the science.

The stem cell science deniers continue to denigrate adult stem cells, denying their successes or even at times their existence by dropping the necessary, descriptive adjective. But for patients, adult stem cells are the true gold standard for stem cells. The hope of adult stem cells is being realized right now, for thousands of people around the globe. Those stories, those doctors, those patients who have been helped by adult stem cell treatments, deserve to be heard. People like Cindy Schroeder who thought she was given a death sentence when she was diagnosed with multiple myeloma.

But Cindys doctor was informed on the facts of modern medicine, and was able to inform Cindy and her family that there was hopefrom adult stem cells. Over a year after her stem cell treatment, Cindy leads a full, active life and her family is closer than ever. Her story, like that of thousands of others, is not theoretical; its real adult stem cell science.

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Hundreds of U.S. clinics are selling unapproved stem cell …

By Stem Cell Clinics

Hundreds of clinics across the United States are marketing unapproved stem cell treatments for conditions ranging from aging skin to spinal cord injuries, a new study finds.

In an online search, researchers found at least 570 clinics offering unapproved stem cell "therapies." They tend to be concentrated in a handful of states -- including Arizona, California, Colorado, Florida, New York and Texas -- but are scattered across many other states, too.

Most often, the clinics market stem cell procedures for orthopedic conditions, such as arthritis and injured ligaments and tendons. This does have science behind it, but is still experimental, medical experts said.

In other cases with little or no supporting evidence, clinics hawked stem cell "facelifts" and therapies for serious conditions such as chronic lung disease, Parkinson's disease and multiple sclerosis.

If these pricey stem cell treatments are unproven and unapproved by federal regulators, how can these clinics exist?

"I ask myself that question all the time," said Leigh Turner, a bioethicist who worked on the study.

Turner, an associate professor at the University of Minnesota's Center for Bioethics, said attention used to focus on "stem cell tourism" -- where people travel to countries such as China, India and Mexico to get unproven treatments.

"I think there's a misperception that everything here [in the U.S.] is regulated," Turner said. "But these clinics are operating here, and on a relatively large scale."

Stem cells are primitive cells with the potential to mature into various types of body tissue. Medical researchers have been studying the possibility of using stem cells to repair damaged tissue in a range of chronic ills -- with limited success so far.

But the general public has heard about the "promise" of stem cells for years, and it can be easy to be taken in by clinics' marketing tactics, Turner said.

Websites can, for instance, link to published medical studies that make their therapies seem legitimate, Turner said. "These businesses can be quite savvy," he said. "I think it's asking too much to just tell consumers to be wary. We need to be asking, why should these clinics be allowed to do this?"

Arthur Caplan, a bioethicist who was not involved in the study, cited some explanations for the growth of stem cell clinics.

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The businesses are usually not engaging in interstate commerce, which helps them "fly under the radar," said Caplan, who directs the division of medical ethics at NYU Langone Medical Center in New York City.

Plus, he said, there's a regulatory gray area when it comes to so-called "autologous" stem cell therapy -- which refers to treatments that use a person's own stem cells.

"If you have cells from your own body reinjected, it isn't clear that you're getting a 'new biologic,' " Caplan explained.

Of the businesses Turner's team found, most marketed autologous therapies, usually using stem cells from people's body fat or bone marrow. But about one-fifth of the businesses claimed to use stem cells from umbilical cord blood or amniotic or placental tissue.

The issue goes beyond people wasting their money or having their "hopes dashed," Turner said. It's known some have been seriously harmed.

He mentioned two elderly patients in Florida who died following an unapproved stem cell procedure.

The U.S. Food and Drug Administration has taken steps against specific businesses. Last year, it sent a warning letter to a network of clinics that operate in California, Florida and New York. According to the FDA, the clinics illegally use stem cells from people's fat tissue to treat conditions such as Parkinson's, MS, amyotrophic lateral sclerosis (ALS) and autism.

"Many of these claims are outrageous," Caplan said. "These clinics are preying on vulnerable people."

His advice for consumers: "Be wary of any procedure that comes with celebrity endorsements or patient testimonials."

The FDA has issued draft guidelines on the use of stem cells. A public hearing is scheduled for later this year.

The new study findings appear in the June 30 issue of Cell Stem Cell.

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