Stem cell

Stem cells are undifferentiated or partially differentiated cells found in multicellular organisms that retain the ability both to self-renew through cell division and to differentiate into specialised cell types. They represent the earliest cells within a developmental lineage and are essential for organismal development, tissue maintenance and regeneration. Stem cells occur in both embryonic and adult tissues, although the properties, potency and biological roles of these two classes differ. Their discovery and characterisation underpin many areas of modern biomedical science, including regenerative medicine, developmental biology and cell-based therapies.

Introduction and Classification

During early mammalian development, a mass of approximately 50 to 150 cells within the blastocyst—known as the inner cell mass—possesses pluripotent capacity. These cells can differentiate into all body cell types via the formation of the three primary germ layers: ectoderm, mesoderm and endoderm during gastrulation. When isolated and cultured in vitro these cells can be maintained in an undifferentiated state and are termed embryonic stem cells (ESCs).
Adult stem cells, by contrast, reside in specialised microenvironments known as stem-cell niches within tissues such as bone marrow, gonads, the basal layer of the skin and certain connective tissues. They maintain and replenish tissues in which cell turnover is rapid or continuous. Examples include haematopoietic stem cells, which generate blood and immune cells; epidermal stem cells in the stratum basale; and mesenchymal stem cells, which give rise to bone, cartilage, muscle and adipose tissues. Adult stem cells are typically multipotent or unipotent and form only a small fraction of the total cell population.
Stem cells are distinct from progenitor and precursor cells. Progenitor cells have limited proliferative capacity and are generally primed for a particular differentiation pathway, whereas precursor or blast cells are usually committed to producing a single cell type.

Historical Development

The conceptual foundations of stem cell biology emerged in the late nineteenth and early twentieth centuries from the work of scientists such as Theodor Boveri, Valentin Haecker, Artur Pappenheim, Alexander Maximow and Franz Neumann. However, the defining experimental evidence came in the 1960s from Ernest McCulloch and James Till at the University of Toronto. By injecting bone marrow cells into irradiated mice, they observed spleen colonies that correlated with the number of transplanted cells and deduced that each colony arose from a single multipotent cell. Subsequent work with Andrew Becker and Louis Siminovitch demonstrated that these colony-forming units had self-renewal capability, establishing the concept of the haematopoietic stem cell.
Therapeutic use of stem cells began with bone marrow transplantation. Georges Mathé carried out the first successful transplant in 1956, treating radiation-exposed workers and demonstrating the clinical potential of haematopoietic stem cells. In 1981 mouse ESCs were isolated and cultured by Martin Evans and Matthew Kaufman, enabling the creation of genetic mouse models. James Thomson isolated human ESCs in 1998, further expanding therapeutic and research possibilities.
In 2006 Shinya Yamanaka’s group in Kyoto demonstrated that adult somatic cells could be reprogrammed to a pluripotent state by modifying the expression of four specific genes. These induced pluripotent stem cells (iPSCs) revolutionised stem cell science by enabling the creation of pluripotent cells without the need for embryos. Their emergence also reshaped ethical debates surrounding embryonic stem cell research.

Properties and Potency

Stem cells are defined by two cardinal properties: self-renewal and differentiation capacity.
Self-renewal allows stem cells to undergo repeated cycles of division while maintaining an undifferentiated state. This can occur through asymmetric cell division—producing one identical stem cell and one cell destined for differentiation—or through symmetric division when population expansion is required. Maintenance of stemness involves strict regulation of the cell cycle and expression of crucial transcription factors. Telomerase activity helps protect chromosome ends, supporting extended proliferative potential beyond the Hayflick limit.
Potency describes the range of cell types a stem cell can produce:

• Totipotent cells can generate all embryonic and extraembryonic tissues, producing a complete organism. Zygotes and early cleavage-stage blastomeres are totipotent.
• Pluripotent cells such as ESCs and iPSCs can form all somatic and germline tissues derived from the three germ layers but not extraembryonic structures.
• Multipotent cells differentiate into a restricted family of related cell types, for example haematopoietic stem cells that form diverse blood cells.
• Unipotent cells produce only one cell type but retain the capacity for self-renewal.

Stem cell function is influenced by feedback mechanisms involving intrinsic genetic regulation and extrinsic signals from the surrounding niche.

Identification and Characterisation

In practice, stem cells are identified by their capacity to regenerate tissue. Haematopoietic stem cells, for example, are defined by their ability to repopulate the blood system of an irradiated recipient in transplantation assays. Successful secondary transplantation further confirms long-term self-renewal.
In vitro, clonogenic assays assess the ability of individual cells to proliferate and differentiate. Distinctive cell surface markers, detected via immunological or flow-cytometric techniques, are frequently used for isolation, although culture conditions can alter cellular properties. Disputes remain over whether some adult cell populations genuinely possess stem cell functionality, illustrating the complexity of defining stemness outside controlled laboratory conditions.

Sources and Ethical Considerations

Embryonic stem cells are obtained from the inner cell mass of blastocysts, and their isolation typically entails destruction of the embryo. This has prompted extensive ethical and legislative debate. Restrictions vary globally, with countries like the UK and China supporting regulated research, while others impose stringent limits. Somatic cell nuclear transfer offers a route to generate patient-specific ESCs but raises additional ethical and regulatory issues.
Adult stem cells, derived from tissues such as bone marrow, adipose tissue or peripheral blood, do not involve embryo destruction and are widely accepted for clinical use. Haematopoietic stem cell transplantation remains the only established stem cell therapy, although research into mesenchymal and neural stem cells continues.
iPSCs circumvent many ethical objections by permitting derivation of pluripotent cells from adult tissues. However, their genetic manipulation and potential for aberrant differentiation require careful assessment.

Applications and Research Directions

Stem cells hold promise in regenerative medicine for repairing tissues damaged by injury or disease. ESCs and iPSCs can be differentiated into diverse specialised cells for transplantation, drug screening or disease modelling. Mouse ESCs underpin genetic engineering techniques used in developmental biology and translational research. Adult stem cells support therapies for haematological malignancies and offer prospects for orthopaedic and neurological interventions.