Research has shown that there are also stem cells in the brain. In mammals very few new neurons are formed after birth, but some neurons in the olfactory bulbs and in the hippocampus are continually being formed. These neurons arise from neural stem cells, which can be cultured in vitro in the form of neurospheres—small cell clusters that contain stem cells and some of their progeny. This type of stem cell is being studied for use in cell therapy to treat Parkinson disease and other forms of neurodegeneration or traumatic damage to the central nervous system.

Somatic cell nuclear transfer

Following experiments in animals, including those used to create Dolly the sheep, there has been much discussion about the use of somatic cell nuclear transfer (SCNT) to create pluripotent human cells. In SCNT the nucleus of a somatic cell (a fully differentiated cell, excluding germ cells), which contains the majority of the cell’s DNA (deoxyribonucleic acid), is removed and transferred into an unfertilized egg cell that has had its own nuclear DNA removed. The egg cell is grown in culture until it reaches the blastocyst stage. The inner cell mass is then removed from the egg, and the cells are grown in culture to form an embryonic stem cell line (generations of cells originating from the same group of parent cells). These cells can then be stimulated to differentiate into various types of cells needed for transplantation. Since these cells would be genetically identical to the original donor, they could be used to treat the donor with no problems of immune rejection. Scientists generated human embryonic stem cells successfully from SCNT human embryos for the first time in 2013.

While promising, the generation and use of SCNT-derived embryonic stem cells is controversial for several reasons. One is that SCNT can require more than a dozen eggs before one egg successfully produces embryonic stem cells. Human eggs are in short supply, and there are many legal and ethical problems associated with egg donation. There are also unknown risks involved with transplanting SCNT-derived stem cells into humans, because the mechanism by which the unfertilized egg is able to reprogram the nuclear DNA of a differentiated cell is not entirely understood. In addition, SCNT is commonly used to produce clones of animals (such as Dolly). Although the cloning of humans is currently illegal throughout the world, the egg cell that contains nuclear DNA from an adult cell could in theory be implanted into a woman’s uterus and come to term as an actual cloned human. Thus, there exists strong opposition among some groups to the use of SCNT to generate human embryonic stem cells.

Induced pluripotent stem cells

Due to the ethical and moral issues surrounding the use of embryonic stem cells, scientists have searched for ways to reprogram adult somatic cells. Studies of cell fusion, in which differentiated adult somatic cells grown in culture with embryonic stem cells fuse with the stem cells and acquire embryonic stem-cell-like properties, led to the idea that specific genes could reprogram differentiated adult cells. An advantage of cell fusion is that it relies on existing embryonic stem cells instead of eggs. However, fused cells stimulate an immune response when transplanted into humans, which leads to transplant rejection.

As a result, research has become increasingly focused on the genes and proteins capable of reprogramming adult cells to a pluripotent state. In order to make adult cells pluripotent without fusing them to embryonic stem cells, regulatory genes that induce pluripotency must be introduced into the nuclei of adult cells. To do this, adult cells are grown in cell culture, and specific combinations of regulatory genes are inserted into retroviruses (viruses that convert RNA [ribonucleic acid] into DNA), which are then introduced to the culture medium. The retroviruses transport the RNA of the regulatory genes into the nuclei of the adult cells, where the genes are then incorporated into the DNA of the cells. About 1 out of every 10,000 cells acquires embryonic stem cell properties. Although the mechanism is still uncertain, it is clear that some of the genes confer embryonic stem cell properties by means of the regulation of numerous other genes. Adult cells that become reprogrammed in this way are known as induced pluripotent stem cells (iPS).

Similar to embryonic stem cells, induced pluripotent stem cells can be stimulated to differentiate into select types of cells that could in principle be used for disease-specific treatments. In addition, the generation of induced pluripotent stem cells from the adult cells of patients affected by genetic diseases can be used to model the diseases in the laboratory. For example, in 2008 researchers isolated skin cells from a child with an inherited neurological disease called spinal muscular atrophy and then reprogrammed these cells into induced pluripotent stem cells. The reprogrammed cells retained the disease genotype of the adult cells and were stimulated to differentiate into motor neurons that displayed functional insufficiencies associated with spinal muscular atrophy. By recapitulating the disease in the laboratory, scientists were able to study closely the cellular changes that occurred as the disease progressed. Such models promise not only to improve scientists’ understanding of genetic diseases but also to facilitate the development of new therapeutic strategies tailored to each type of genetic disease.

In 2009 scientists successfully generated retinal cells of the human eye by reprogramming adult skin cells. This advance enabled detailed investigation of the embryonic development of retinal cells and opened avenues for the generation of novel therapies for eye diseases. The production of retinal cells from reprogrammed skin cells may be particularly useful in the treatment of retinitis pigmentosa, which is characterized by the progressive degeneration of the retina, eventually leading to night blindness and other complications of vision. Although retinal cells also have been produced from human embryonic stem cells, induced pluripotency represents a less controversial approach. Scientists have also explored the possibility of combining induced pluripotent stem cell technology with gene therapy, which would be of value particularly for patients with genetic disease who would benefit from autologous transplantation.

Researchers have also been able to generate cardiac stem cells for the treatment of certain forms of heart disease through the process of dedifferentiation, in which mature heart cells are stimulated to revert to stem cells. The first attempt at the transplantation of autologous cardiac stem cells was performed in 2009, when doctors isolated heart tissue from a patient, cultured the tissue in a laboratory, stimulated cell dedifferentiation, and then reinfused the cardiac stem cells directly into the patient’s heart. A similar study involving 14 patients who underwent cardiac bypass surgery followed by cardiac stem cell transplantation was reported in 2011. More than three months after stem cell transplantation, the patients experienced a slight but detectable improvement in heart function.

Patient-specific induced pluripotent stem cells and dedifferentiated cells are highly valuable in terms of their therapeutic applications because they are unlikely to be rejected by the immune system. However, before induced pluripotent stem cells can be used to treat human diseases, researchers must find a way to introduce the active reprogramming genes without using retroviruses, which can cause diseases such as leukemia in humans. A possible alternative to the use of retroviruses to transport regulatory genes into the nuclei of adult cells is the use of plasmids, which are less tumorigenic than viruses.

In 2021 multiple research teams, working independently, generated human blastocyst-like structures in vitro. The structures were grown using different types of cell populations, including human embryonic stem cells, iPS cells, and reprogrammed adult skin cells. The breakthrough provided a novel means of studying human embryonic development and the very early stages of pregnancy.

Jonathan M.W. Slack

regenerative medicine, the application of treatments developed to replace tissues damaged by injury or disease. These treatments may involve the use of biochemical techniques to induce tissue regeneration directly at the site of damage or the use of transplantation techniques employing differentiated cells or stem cells, either alone or as part of a bioartificial tissue. Bioartificial tissues are made by seeding cells onto natural or biomimetic scaffolds (see tissue engineering). Natural scaffolds are the total extracellular matrixes (ECMs) of decellularized tissues or organs. In contrast, biomimetic scaffolds may be composed of natural materials, such as collagen or proteoglycans (proteins with long chains of carbohydrate), or built from artificial materials, such as metals, ceramics, or polyester polymers. Cells used for transplants and bioartificial tissues are almost always autogeneic (self) to avoid rejection by the patient’s immune system. The use of allogeneic (nonself) cells carries a high risk of immune rejection and therefore requires tissue matching between donor and recipient and involves the administration of immunosuppressive drugs.

Cell and bioartificial tissue transplantation

A variety of autogeneic and allogeneic cell and bioartificial tissue transplantations have been performed. Examples of autogeneic transplants using differentiated cells include blood transfusion with frozen stores of the patient’s own blood and repair of the articular cartilage of the knee with the patient’s own articular chondrocytes (cartilage cells) that have been expanded in vitro (amplified in number using cell culture techniques in a laboratory). An example of a tissue that has been generated for autogeneic transplant is the human mandible (lower jaw). Functional bioartificial mandibles are made by seeding autogeneic bone marrow cells onto a titanium mesh scaffold loaded with bovine bone matrix, a type of extracellular matrix that has proved valuable in regenerative medicine for its ability to promote cell adhesion and proliferation in transplantable bone tissues. Functional bioartificial bladders also have been successfully implanted into patients. Bioartificial bladders are made by seeding a biodegradable polyester scaffold with autogeneic urinary epithelial cells and smooth muscle cells.

Another example of a tissue used successfully in an autogeneic transplant is a bioartificial bronchus, which was generated to replace damaged tissue in a patient affected by tuberculosis. The bioartificial bronchus was constructed from an ECM scaffold of a section of bronchial tissue taken from a donor cadaver. Differentiated epithelial cells isolated from the patient and chondrocytes derived from mesenchymal stem cells collected from the patient’s bone marrow were seeded onto the scaffold.

There are few clinical examples of allogeneic cell and bioartificial tissue transplants. The two most common allogeneic transplants are blood-group-matched blood transfusion and bone marrow transplant. Allogeneic bone marrow transplants are often performed following high-dose chemotherapy, which is used to destroy all the cells in the hematopoietic system in order to ensure that all cancer-causing cells are killed. (The hematopoietic system is contained within the bone marrow and is responsible for generating all the cells of the blood and immune system.) This type of bone marrow transplant is associated with a high risk of graft-versus-host disease, in which the donor marrow cells attack the recipient’s tissues. Another type of allogeneic transplant involves the islets of Langerhans, which contain the insulin-producing cells of the body. This type of tissue can be transplanted from cadavers to patients with diabetes mellitus, but recipients require immunosuppression therapy to survive.

Cell transplant experiments with paralyzed mice, pigs, and nonhuman primates demonstrated that Schwann cells (the myelin-producing cells that insulate nerve axons) injected into acutely injured spinal cord tissue could restore about 70 percent of the tissue’s functional capacity, thereby partially reversing paralysis.

Regeneration using stem cells

Studies on experimental animals are aimed at understanding ways in which autogeneic or allogeneic adult stem cells can be used to regenerate damaged cardiovascular, neural, and musculoskeletal tissues in humans. Among adult stem cells that have shown promise in this area are satellite cells, which occur in skeletal muscle fibres in animals and humans. When injected into mice affected by dystrophy, a condition characterized by the progressive degeneration of muscle tissue, satellite cells stimulate the regeneration of normal muscle fibres. Ulcerative colitis in mice was treated successfully with intestinal organoids (organlike tissues) derived from adult stem cells of the large intestine. When introduced into the colon, the organoids attached to damaged tissue and generated a normal-appearing intestinal lining.

In many cases, however, adult stem cells such as satellite cells have not been easily harvested from their native tissues, and they have been difficult to culture in the laboratory. In contrast, embryonic stem cells (ESCs) can be harvested once and cultured indefinitely. Moreover, ESCs are pluripotent, meaning that they can be directed to differentiate into any cell type, which makes them an ideal cell source for regenerative medicine.

Are you a student?
Get a special academic rate on Britannica Premium.

Studies of animal ESC derivatives have demonstrated that these cells are capable of regenerating tissues of the central nervous system, heart, skeletal muscle, and pancreas. Derivatives of human ESCs used in animal models have produced similar results. For example, cardiac stem cells from heart-failure patients were engineered to express a protein (Pim-1) that promotes cell survival and proliferation. When these cells were injected into mice that had experienced myocardial infarction (heart attack), the cells were found to enhance the repair of injured heart muscle tissue. Likewise, heart muscle cells (cardiomyocytes) derived from human ESCs improved the function of injured heart muscle tissue in guinea pigs.

Derivatives of human ESCs are likely to produce similar results in humans, although these cells have not been used clinically and could be subject to immune rejection by recipients. The question of immune rejection was bypassed by the discovery in 2007 that adult somatic cells (e.g., skin and liver cells) can be converted to ESCs. This is accomplished by transfecting (infecting) the adult cells with viral vectors carrying genes that encode transcription factor proteins capable of reprogramming the adult cells into pluripotent stem cells. Examples of these factors include Oct-4 (octamer 4), Sox-2 (sex-determining region Y box 2), Klf-4 (Kruppel-like factor 4), and Nanog. Reprogrammed adult cells, known as induced pluripotent stem (iPS) cells, are potential autogeneic sources for cell transplantation and bioartificial tissue construction. Such cells have since been created from the skin cells of patients suffering from amyotrophic lateral sclerosis (ALS) and Alzheimer disease and have been used as human models for the exploration of disease mechanisms and the screening of potential new drugs. In one such model, neurons derived from human iPS cells were shown to promote recovery of stroke-damaged brain tissue in mice and rats, and, in another, cardiomyocytes derived from human iPS cells successfully integrated into damaged heart tissue following their injection into rat hearts. These successes indicated that iPS cells could serve as a cell source for tissue regeneration or bioartificial tissue construction.