Stem cell

• 1. Introduction

  ›

  Stem cells hold a property that virtually no other cell in the body possesses: the ability to become almost anything. A single stem cell can divide and produce daughter cells that turn into heart muscle, nerve tissue, bone, or blood, depending on the signals it receives. That capacity for transformation raises a question that has driven scientists, patients, ethicists, and governments into decades of conflict. What exactly is a stem cell, where do they come from, and how close are we to using them to heal the human body? Those questions thread through a story that begins in the mid-20th century and remains unresolved today.

• 2. Toronto and the First Proof

  ›

  Ernest McCulloch and James Till, working at the University of Toronto's Faculty of Medicine and the Ontario Cancer Institute in the early 1960s, were the first to rigorously define what a stem cell actually does. Their approach was direct and somewhat brutal: they injected bone marrow cells into mice that had been irradiated, damaging the animals' blood-forming systems. What they observed in the spleens of those mice were discrete lumps, each proportional in number to the quantity of bone marrow cells that had been injected.

  McCulloch and Till hypothesized that each lump was a colony grown from a single marrow cell. That was a daring claim. To test it, they brought in graduate student Andrew John Becker and senior scientist Louis Siminovitch. Together, the four confirmed that each colony did indeed arise from one cell. Their results appeared in Nature in 1963. That same year, Siminovitch led studies showing that these colony-forming cells could also renew themselves, which is the second defining property of a stem cell alongside the capacity to differentiate.

  The term itself was older. Theodor Boveri and Valentin Haecker had coined the phrase in the late 19th century, and early 20th-century researchers including Artur Pappenheim, Alexander A. Maximow, and Franz Ernst Christian Neumann had theorized about blood-forming stem cells. But the Toronto experiments turned theory into measurable biology. The first therapeutic use of a stem cell, a bone marrow transplant conducted by French oncologist Georges Mathé in 1956, had already preceded this formal proof. Mathé treated five workers from the Vinča Nuclear Institute in Yugoslavia who had been injured in a criticality accident, and all five survived.

• 3. Embryonic Cells and the Controversy

  ›

  In 1981, British biologists Martin Evans and Matthew Kaufman successfully isolated embryonic stem cells from mouse blastocysts and kept them alive in culture. That achievement opened the door to murine genetic models, a research system in which genes in mice are deleted or altered to reveal their role in disease. By 1991, Ann Tsukamoto patented a process for isolating human stem cells. By 1998, American biologist James Thomson had isolated the first human embryonic stem cells, making it possible to contemplate new transplantation methods and platforms for testing new treatments.

  But the method of obtaining those cells sits at the center of a deep ethical dispute. Deriving embryonic stem cells typically requires destroying the early-stage embryo. Critics argue this violates the sanctity of human life. Several European nations and Canada have restricted the sources from which these cells can be obtained, while countries including the United Kingdom and China have actively promoted the research. Roman Catholic teaching explicitly forbids the use of embryonic stem cells in experiments, and the Vatican newspaper Osservatore Romano described amniotic stem cells, an alternative source, as "the future of medicine."

  In the United States, the regulatory picture is shaped by Executive Order 13505, which allows federal money to support research using approved human embryonic stem cell lines but bars the use of federal funds to derive new lines. The National Institutes of Health Guidelines that gave effect to the order took effect on the 7th of July 2009. As of January 2022, there were 486 lines approved for NIH funding.

• 4. A New Route: Reprogramming

  ›

  In 2006, a team led by Shinya Yamanaka at Kyoto University announced something that had seemed impossible: they had taken ordinary mouse fibroblast cells and converted them back into a pluripotent state using just four transcription factors, Oct3/4, Sox2, c-Myc, and Klf4. These induced pluripotent stem cells, or iPSCs, behaved like embryonic stem cells without requiring the destruction of an embryo.

  Subsequent work extended the finding to human cells. Junying Yu, James Thomson, and colleagues at the University of Wisconsin-Madison used a different set of factors, Oct4, Sox2, Nanog, and Lin28, and worked with cells from human foreskin, arriving at the same result by a different route. The announcement's reach spread quickly. Ian Wilmut, who had helped create Dolly the Sheep and who had championed somatic cell nuclear transfer as a path to therapeutic stem cells, announced he would abandon that avenue in light of the reprogramming breakthrough.

  IPSCs share most of the properties of embryonic stem cells, including pluripotency, the ability to form embryoid bodies and teratomas, and expression of pluripotency genes. But differences remain. The chromatin of iPSCs is more methylated, or chemically closed, than that of embryonic stem cells. The gene expression patterns between the two cell types differ, as do iPSCs derived from different tissue sources. Researchers describe these gaps as questions about the completeness of reprogramming and the degree to which a reprogrammed cell retains a memory of its original identity. The efficiency of reprogramming is also low and is correlated with the number of cell divisions that occur during the process, which partly explains why reprogramming works less reliably in older or slow-dividing cells.

• 5. The Body's Own Reserves

  ›

  Adult stem cells live in small, protected compartments within the body called niches. Bone marrow and the gonads are among the known niche locations. Unlike embryonic stem cells, adult stem cells are typically multipotent or unipotent, meaning each one can produce only a limited range of cell types rather than the full body repertoire.

  Hematopoietic stem cells replenish blood and immune cells. Basal cells maintain the skin's epithelial layer. Mesenchymal stem cells sustain bone, cartilage, muscle, and fat tissue. Treatment with hematopoietic stem cells, usually through bone marrow transplantation, has been practiced for more than 50 years as the established therapy for leukaemia and lymphoma. Bone marrow stem cells have also been applied in treating liver cirrhosis, chronic limb ischemia, and end-stage heart failure.

  The quantity of bone marrow stem cells is not fixed across a lifetime. It declines with age and is higher in males than in females during the reproductive years. DNA damage accumulates in stem cells over time, and this accumulation is thought to contribute to rising stem cell dysfunction in older individuals. Hematopoietic stem cells in particular are vulnerable to genetic mutations that increase with age, which may help explain the greater incidence of slow-growing blood cancers in older patients.

  A more recently identified adult type, called muse cells (multi-lineage differentiating stress enduring cells), has been found in adipose tissue, dermal fibroblasts, and bone marrow. These cells are rare and identifiable by their expression of SSEA-3 and mesenchymal markers including CD90 and CD105. When cultured in single-cell suspension, they form clusters that resemble embryoid bodies and express pluripotency markers Oct4, Sox2, and Nanog.

• 6. Therapy and Its Limits

  ›

  Hematopoietic stem cell transplantation, first performed by Georges Mathé in 1956, remains the only widely established stem cell therapy in clinical medicine. Bone marrow transplant is its most common form, though cells derived from umbilical cord blood are also used. Research is active for applications targeting neurodegenerative conditions, diabetes, and heart disease, and stem cell implantation has shown potential for strengthening the left ventricle of the heart in patients who have had heart attacks.

  The US Food and Drug Administration approved the first human trial of embryonic stem cell therapy in January 2009. The trial itself did not begin until the 13th of October 2010, in Atlanta, where it addressed spinal cord injury. On the 14th of November 2011, Geron Corporation, which was conducting the trial, announced it would discontinue its stem cell programs.

  Among the practical obstacles is tumor formation. Pluripotent stem cells, including embryonic stem cells and iPSCs, can cause teratomas if injected directly into the body without proper differentiation signals. Fetal proper stem cells can also form tumors despite being only multipotent. Achieving the specific cell type required for treatment is difficult because cells in a population do not all differentiate uniformly. Transplant rejection is another risk unless the cells come from the patient's own body.

  Outside regulated medicine, a different problem has grown. In the United States, clinics offering stem cell procedures have multiplied rapidly. The International Society for Stem Cell Research, the largest academic organization in the field, has stated that these therapies remain under development and cannot yet be described as proven. Patients who have undergone procedures at unregulated clinics have experienced complications including spinal tumors.

• 7. What Stem Cells Can Become

  ›

  Potency is the formal term for how much a stem cell can become. Totipotent cells, produced by the early divisions of a fertilized egg, can build an entire viable organism, including the extraembryonic membranes. Pluripotent cells are descendants of totipotent cells and can become any of the more than 200 cell types of the adult body, drawn from all three germ layers, though not the extraembryonic structures. Multipotent cells are limited to a family of related cell types. Oligopotent cells can produce only a few types, such as lymphoid or myeloid cells. Unipotent cells generate only one type but retain the property of self-renewal, which distinguishes them from non-stem cells.

  Self-renewal itself relies on two distinct mechanisms. Asymmetric cell division produces one daughter cell that retains stem cell properties and one that is committed to differentiation. Symmetric division generates two identical stem cell daughters, expanding the stem cell pool. Stem cells also use telomerase, a protein that restores the protective caps on chromosomes called telomeres, allowing them to divide far beyond the limit that constrains ordinary cells.

  Embryonic stem cells have a distinctive cell cycle. Their doubling time runs between 8 and 10 hours, compared to roughly 20 hours or longer for somatic cells. This speed comes partly from a dramatically shortened G1 phase, the period in which cells are most susceptible to differentiation signals. In mouse embryonic stem cells, the Cyclin E/Cdk2 complex is active throughout the entire cell cycle rather than in the limited window where it operates in ordinary cells, which keeps the retinoblastoma protein hyperphosphorylated and inactive and allows cells to jump directly into later phases. The discovery that dormancy mechanisms also regulate certain stem cells, published by researchers at the Princess Margaret Cancer Centre at the University Health Network in August 2021, suggested new angles for developing cancer treatments.