Stem cell types and what distinguishes them: pluripotent, mesenchymal, haematopoietic, neural and cancer
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The word "stem cell" is used so broadly that it can obscure more than it reveals. In press coverage and investor pitch decks alike, the term often appears without qualification, as though all stem cells were interchangeable. They are not. Different stem cell types differ in where they come from, what they can become, how long they persist, and what they are useful for. Knowing which type you are dealing with, and what it can and cannot do, is fundamental to building, using, or evaluating any technology in this space.
This article describes the major categories in functional terms: what distinguishes them, where they sit in the developmental hierarchy, and which applications each is relevant to.
What makes a cell a stem cell
Two properties define a stem cell. The first is self-renewal: the ability to divide and produce at least one daughter cell that retains the same properties as the parent. The second is potency: the ability to give rise to more specialised cell types through differentiation [1].
Not all stem cells have the same degree of potency. A fertilised egg and the cells of the very early embryo are totipotent, meaning they can give rise to every cell type in the body plus the extra-embryonic tissues such as the placenta. But importantly the fertilised egg is not a stem cell because after it divides neither of the daughter cells which result are like the cell they came from. No stem cell line maintained in the laboratory is truly totipotent. The most potent cells available for research and therapy are pluripotent, which can produce all cell types of the body but not the extra-embryonic structures. Further down the hierarchy, multipotent cells can generate several related cell types within a particular tissue lineage, and unipotent cells produce only one [1,2].
These are not fixed labels. The boundaries between categories are less sharp than textbooks sometimes imply, and the conditions under which cells are cultured can shift where they sit.
Pluripotent stem cells
Pluripotent stem cells (PSCs) sit near the top of the potency hierarchy. They can, in principle, form any cell type of the three embryonic germ layers: ectoderm (which gives rise to skin and nervous system), mesoderm (muscle, bone, blood, heart), and endoderm (gut, liver, lungs). There also exist distinct states of pluripotency, naive and primed, which are mutable and impact on their maintenance and use [1].
Presently, there are two main sources. Embryonic stem cells (ESCs) are derived from the inner cell mass of a blastocyst-stage embryo, typically around five to six days after fertilisation in humans. James Thomson and colleagues at the University of Wisconsin first isolated stable human ESC lines in 1998 [3]. This achievement opened the prospect of using human cells to model development, screen drugs, and potentially replace damaged tissue.
Induced pluripotent stem cells (iPSCs) are produced by reprogramming adult somatic cells, a process first achieved in mouse fibroblasts by Kazutoshi Takahashi and Shinya Yamanaka in 2006, and in human cells the following year [4,5]. The reprogramming involved introducing a defined set of transcription factor genes, originally Oct3/4, Sox2, Klf4, and c-Myc, that reset the cell's gene expression programme to a pluripotent state. Yamanaka shared the 2012 Nobel Prize in Physiology or Medicine with John Gurdon for demonstrating that cellular identity is more plastic than previously thought. Gurdon first demonstrated this by cloning tadpoles by transfer of intestinal somatic cell nuclei into frog eggs [6].
ESC and iPSC have broad similarities, to the extent that methods and tools developed for one generally translate with some caveats. Importantly, they are not identical and their provenance impacts on their properties and use. More on that in future blogs. For today, iPSCs are now the more dominant source of pluripotent cells for research and many translational applications, largely because they can be generated from any individual, enabling patient-specific disease modelling [7].
Both ESCs and iPSCs can be expanded indefinitely in culture, a property that is critical for scaling manufacturing. They are also a choice starting material for most directed differentiation protocols, where specific cocktails of growth factors and small molecules guide the cells toward a target cell type. The quality, consistency, and safety of these starting materials are central concerns for any technology that depends on them [8].
Mesenchymal stromal cells
Mesenchymal stromal cells (MSCs), sometimes called mesenchymal stem cells, are multipotent cells that can differentiate into bone, cartilage, and fat cells. They are found in many tissues, including bone marrow, adipose tissue, umbilical cord, and dental pulp [9].
MSCs attracted early clinical interest because they are relatively easy to isolate and expand, they appear to modulate immune responses, and they secrete factors that promote tissue repair. Hundreds of clinical trials have used MSCs for conditions ranging from graft-versus-host disease to osteoarthritis and heart failure, and many more chronic and acute conditions [10].
However, the field has been complicated by inconsistent nomenclature, variable cell characterisation and properties depending on their origin. The International Society for Cell and Gene Therapy (ISCT) proposed minimum criteria for defining MSCs in 2006, based on plastic adherence, surface marker expression, and trilineage differentiation potential [11]. These criteria were useful but imperfect. Cells meeting the same criteria from different tissues can behave differently, and the term MSC has been applied to populations that may not all be genuinely stem cells in the strict sense of self-renewal and multipotency [9].
MSCs can also be derived from pluripotent stem cells. This approach offers a more renewable and standardised source compared to adult tissue donors, with potentially greater consistency across batches. This is relevant for manufacturing applications where lot-to-lot variability is a significant barrier [8].
Haematopoietic stem cells
Haematopoietic stem cells (HSCs) are the stem cells of the blood system. They reside primarily in the bone marrow and give rise to all blood cell lineages: red blood cells, platelets, and the full range of white blood cells including those of the innate and adaptive immune systems [12].
HSC transplantation, commonly referred to as bone marrow transplantation, has been used clinically since the late 1960s and remains the most established stem cell therapy. It is the standard of care for certain blood cancers, bone marrow failure syndromes, and severe immune deficiencies. The success of HSC transplantation rests on the ability of donor HSCs to engraft in the recipient's bone marrow and reconstitute the entire blood system [12].
Understanding HSC biology has been central to stem cell science more broadly. Much of the conceptual framework for stem cell hierarchies, including the distinction between long-term and short-term self-renewal and the stepwise loss of potency through progenitor stages, was first worked out in the haematopoietic system [13].
Neural stem cells
Neural stem cells (NSCs) are multipotent cells found in specific regions of the developing and adult brain. They generate the three main cell types of the central nervous system: neurons, astrocytes, and oligodendrocytes [14].
In the developing embryo, NSCs are abundant and responsible for producing the extraordinary cellular diversity of the brain and spinal cord. In adults, NSC activity is much more restricted, persisting mainly in the subventricular zone adjacent to the lateral ventricles and the subgranular zone of the hippocampal dentate gyrus [14].
The limited regenerative capacity of the adult brain is one reason that neurodegenerative diseases are so devastating and so difficult to treat. Clinical interest in NSCs focuses on the possibility of replacing lost neurons or supporting glial cells in conditions such as Parkinson's disease, and on understanding why the brain's own repair mechanisms are so constrained relative to other tissues.
Cancer stem cells
The cancer stem cell (CSC) hypothesis proposes that within many tumours, a subpopulation of cells possesses stem-like properties: self-renewal, the ability to differentiate into the varied cell types that make up the bulk of the tumour, and resistance to conventional therapies [15].
The concept was first demonstrated experimentally in acute myeloid leukaemia (AML) by John Dick and colleagues in 1997, who showed that only a specific subset of leukaemia cells could initiate the disease when transplanted into immunodeficient mice [16]. Evidence for CSCs has since been reported in solid tumours including those of the breast, brain, colon, and pancreas.
If the CSC model is correct, it has significant implications for treatment. Standard chemotherapy and radiotherapy may kill the bulk of tumour cells while leaving CSCs intact, enabling relapse. Targeting CSCs specifically would require tools that can distinguish them from both normal stem cells and the non-stem cells of the tumour. This remains a significant technical and biological challenge [15].
Why the distinctions matter
For anyone building, funding, or regulating technologies in the stem cell space, the type of stem cell determines almost everything about the technical requirements, the regulatory pathway, the manufacturing process, and the clinical or commercial viability.
Pluripotent stem cells require complex, tightly controlled culture conditions and extensive quality assurance to ensure genetic and epigenetic stability over prolonged expansion. MSCs are simpler to culture but harder to standardise across tissue sources and donors. HSCs have the longest clinical track record but their expansion in culture remains difficult. NSCs are challenging to access and maintain. Each type brings its own set of enabling technologies, limiting bottlenecks, and unmet needs.
The ancillary technologies that serve this field, culture systems, characterisation tools, bioreactors, delivery platforms, and cryopreservation methods, are not one-size-fits-all. What works for expanding ESC and iPSCs in suspension culture may be inappropriate for maintaining HSCs or differentiating MSCs. Understanding the biology of the cell type you are serving is not supplementary to product development. It is the foundation. Pillar 2 examines what happens when this foundation is insufficient, and why ancillary technologies for stem cell science fail.
References
[1] Wolpert L, Tickle C, Martinez Arias A, Placzek M. Wolpert's Principles of Development. 7th ed. Oxford University Press; 2024.
[2] Smith A. A glossary for stem-cell biology. Nature. 2006;441(7097):1060. DOI: 10.1038/nature04954
[3] Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145-1147. DOI: 10.1126/science.282.5391.1145
[4] Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663-676. DOI: 10.1016/j.cell.2006.07.024
[5] Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861-872. DOI: 10.1016/j.cell.2007.11.019
[6] Gurdon JB. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J Embryol Exp Morphol. 1962;10(4):622-640. DOI: 10.1242/dev.10.4.622
[7] Shi Y, Inoue H, Wu JC, Yamanaka S. Induced pluripotent stem cell technology: a decade of progress. Nat Rev Drug Discov. 2017;16(2):115-130. DOI: 10.1038/nrd.2016.245
[8] De Sousa PA, Steeg R, Kreisel B, Allsopp TE. Hot Start to European Pluripotent Stem Cell Banking. Trends Biotechnol. 2017;35(7):573-576. DOI: 10.1016/j.tibtech.2017.03.004
[9] Viswanathan S, Shi Y, Galipeau J, et al. Mesenchymal stem versus stromal cells: International Society for Cell and Gene Therapy (ISCT) Mesenchymal Stromal Cell committee position statement on nomenclature. Cytotherapy. 2019;21(10):1019-1024. DOI: 10.1016/j.jcyt.2019.08.002
[10] Galipeau J, Sensebe L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell. 2018;22(6):824-833. DOI: 10.1016/j.stem.2018.05.004
[11] Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-317. DOI: 10.1080/14653240600855905
[12] Eaves CJ. Hematopoietic stem cells: concepts, definitions, and the new reality. Blood. 2015;125(17):2605-2613. DOI: 10.1182/blood-2014-12-570200
[13] Weissman IL, Shizuru JA. The origins of the identification and isolation of hematopoietic stem cells, and their capability to induce donor-specific transplantation tolerance and treat autoimmune diseases. Blood. 2008;112(9):3543-3553. DOI: 10.1182/blood-2008-08-078220
[14] Bond AM, Ming GL, Song H. Adult mammalian neural stem cells and neurogenesis: five decades later. Cell Stem Cell. 2015;17(4):385-395. DOI: 10.1016/j.stem.2015.09.003
[15] Batlle E, Clevers H. Cancer stem cells revisited. Nat Med. 2017;23(10):1124-1134. DOI: 10.1038/nm.4409
[16] Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730-737. DOI: 10.1038/nm0797-730
About StemCells.Help
StemCells.Help is an advisory consultancy that aids innovation and real-world impact of life science applications built on developmental and stem cell biology. Founded by Dr Paul De Sousa, it draws on over four decades of experience spanning early embryo development, animal cloning, pluripotent stem cell manufacturing, and technology commercialisation. If you build tools for these domains or work in an emerging application where the biology is the enabling technology, StemCells.Help can provide experienced scientific counsel to ground your decisions. To discuss your needs, talk to Paul.
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