Naturally occurring stem cells in the body are not pluripotent (the pluripotent cells of the early embryo are transiently existing cells, not stem cells). To distinguish them from embryonic stem cells, our natural tissue stem cells are often loosely called adult stem cells. Usually multipotent, they typically give rise to the various types of differentiated cell within the tissue they reside in, and their job is to ensure production of suitable differentiated cells as replacements for cells lost from the tissue (normally through natural turnover). That is, they are principally tissue-specific stem cells; a stem cell in intestinal epithelium does not make hepatocytes or muscle cells, for example.
Stem cells are conspicuously lacking in tissues and organs where there is a very low rate of cell turnover, such as in the adult brain (where neurons are very long-lived). Conversely, they are prominent in tissues with a high cell turnover, notably the epithelium lining the small intestine (where cells are renewed roughly every four days), the epidermis of the skin (cells are renewed about once a fortnight), and blood cells. As detailed below, the cells in these tissues are each capable of being maintained by a single type of stem cell.
Tissue-specific stem cells are maintained in special supportive microenvironments, called stem cell niches, where chemical signals are conveyed from neighboring cells and extracellular matrix to receptors on the stem cell to support stem cell activity and renewal (and to suppress stem cell differentiation). In tissues that are subject to significant mechanical, chemical, and environmental assault the stem cell niches are located in deep-lying regions for protection, and may be protected by neighboring cells from microbial attack. We give some examples below of some of the more commonly studied tissue stem cells. (Note that much of our information on tissue stem cells comes from studies on mice where it is possible to label specific cells and trace their progeny).
Bone marrow stem cells
Human blood cells are initially made in certain embryonic structures before the fetal liver takes over production. From fetal week 20 onward, blood cells originate from the bone marrow, where two types of stem cell have long been known.
• Hematopoietic stem cells (HSCs) are multipotent stem cells anchored to fibro blast-like osteoblasts of the “spongy” inner marrow of the long bones, such as the femur. Studies in mice indicate that a single type of HSC is capable of making all the different blood cells: after a mouse’s bone marrow cells have been destroyed by radiation, a graft of purified HSCs from another mouse allows the incoming cells to differentiate and re-populate the blood. Only about 1 in 10,000 to 15,000 bone marrow cells is an HSC; the frequency in blood is ~1 in 100,000. HSCs are naturally multipotent, ultimately producing all of the terminally differentiated blood cells plus some tissue cells that work in the immune system.
• Mesenchymal stem cells (MSCs) are stromal cells found not just in bone marrow but in organs throughout the body. Bone marrow MSCs (also known as bone mar row stromal cells) are poorly defined and heterogeneous, and unlike HSCs they do not self-renew quite so regularly, but are relatively long-lived. In artificial culture conditions, MSCs derived from the bone marrow can give rise to a variety of cell types, including cartilage, fat, and fibrous connective tissue, as well as bone, but in vivo their normal function is likely to be focused on the gradual turnover of bone. Umbilical cord MSCs have a particularly broad potency in vitro.
Epidermal and intestinal stem cells
In mammals, epidermal stem cells are known to occur in three locations, of which those in the bulge region of the hair follicles give rise to both the hair follicle and to epidermis (Figure 1A). The stem cells that will form epidermis give rise to keratinocytes that progressively differentiate as they move toward upper layers. In the epithelium of the small intestine, stem cells are located near the base of intestinal crypts, small pits that are interspersed between the fingerlike villi that protrude into the lumen (Figure 1B and C).
Fig1. Epidermal and intestinal stem cell locations. (A) Epidermal stem cells can be found in three types of niche: in the bulge region of the hair follicle, the sebaceous gland, and the basal layer of the epidermis (where they produce proliferating transit amplifying cells that, in turn, give rise to increasingly differentiated upper cell layers). (B) Intestinal stem cells (called crypt base columnar or CBC stem cells) are protected by being located at the base of pits (crypts) positioned next to fingerlike projections (villi) that extend into the lumen. They are identified by testing positive for LGR5, a type of G-protein-coupled receptor. They alternate with Paneth cells (which defend the crypt base against microbes by secreting antimicrobial peptides [defensins] and proteins [including lysozyme]). (C) CBC stem cells generate all the cells at the base of the crypt, plus rapidly proliferating, but short-lived, transit amplifying (TA) cells, which occupy the remainder of the crypt. TA cells differentiate into the various functional cells on the villi (enterocytes, tuft cells, goblet cells, and enteroendocrine cells) to replace the epithelial cells that are continuously shed at the villus tip. The +4 “reserve” stem cells (which occupy the fourth position from the crypt base) can restore the LGR5-positive (LGR5+) CBC stem cell compartment following injury. Epithelial turnover occurs about every 4 days. New Paneth cells are supplied every 3–6 weeks. Note that TA cells migrate upwards out of the crypt and up into the villi to produce desired differentiated cells to replace the cells constantly being shed from villi. (A, courtesy of The Graduate School of Biomedical Science, University of Medicine and Dentistry of New Jersey; C, from Barker N [2014] Nat Rev Mol Cell Biol 15:19–33; PMID 24326621. With permission from Springer Nature. Copyright © 2014.)
In order to be able to self-renew, the stem cells rely on receiving chemical signals, often members of the Wnt protein family, from neighboring cells in their niche. These signals may be transmitted by different types of neighboring cells (as in the case of intestinal stem cells) or by neighboring stem cells (as in the case of stem cells in the epidermal basal layer); see Figure 2.
Fig2. Stem cell renewal is often regulated by Wnt signaling within stem cell niches. (A) Intestinal stem cell niche. Components of the CBC (crypt base columnar) stem cell niche at the crypt base include neighboring Paneth cells and pericryptal stromal cells, which supply factors—Wnt proteins, the Notch ligand Delta-like 1 (DLL4), epidermal growth factor (EGF), and Noggin— to regulate the survival and function of the CBC stem cells in vivo. TA cell, transit amplifying cell. (B) Epidermal basal layer stem cell niche. Within the interfollicular epidermis, basal layer stem cells act as their own niche: by expressing ligands for Wnt proteins they continuously induce their own self-renewal. Basal stem cells also express long-range antagonists of Wnt proteins that diffuse to suprabasal layers, basally limiting the Wnt signaling field and “self-organizing” the stratified epidermal architecture. (C) How a local Wnt protein signal induces asymmetric cell division. A cell exposed to a local, extracellular Wnt signal distributes Wnt signaling pathway components to the side of the cell receiving the Wnt protein signal. This orients the mitotic spindle and centrosomes during cell division. The daughter cell close to the Wnt source maintains nuclear β-catenin and stem cell gene expression; the daughter cell remote from the Wnt protein signal loses expression of such genes. APC, adenomatous polyposis coli protein. (A, adapted from Barker N [2014] Nat Rev Mol Cell Biol 15:19–33; PMID 24326621. With permission from Springer Nature. Copyright © 2014; B and C, from Clevers H et al. [2014] Science 346:1248012; PMID 25278615. Reprinted with permission from the AAAS.)
