Table 1.

Glossary and definition of terminology

Potency: Sum of developmental or differentiation capacity of a single cell in its normal environment in vivo in the embryo or adult tissue. A change in potency may occur by dedifferentiation or reprogramming, after transplantation to another site or in response to local inflammation or injury. Demonstrating this change in potency requires lineage tracing the fate of single cells.

Totipotency: The capacity of a single cell to divide and produce all the differentiated cells in an organism, including extraembryonic tissues and germ cells, and thus to (re)generate an organism. In mammals, with rare exceptions, only the zygote and early cleavage blastomeres are totipotent.

Pluripotency: The capacity of a single cell to give rise to differentiated cell types within all three embryonic germ layers and thus to form all lineages of an organism. A classic example is pluripotent embryo-derived stem cells (ESCs). However, some species differences can occur; for example, mouse ESCs do not give rise to extraembryonic cell types, but human ESCs can give rise to trophoblasts.

Multipotency: Ability of a cell to form multiple cell types of one or more lineages. Example: hematopoietic stem cells in adults and neural crest cells in developing embryos

Unipotency: Ability of a cell to give rise to cell types within a single lineage. Example: spermatogonial stem cells can only generate sperm or sperm-precursor intermediate cells.

Lineage: Differentiated cells in a tissue related to each other by descent from a common precursor cell.

Reprogramming: Change in phenotype of a cell so that its differentiation state or potency is altered. At least two kinds of reprogramming have been described. In one, the term refers to a process that involves an initial process of dedifferentiation to a state with greater potency, as in the formation of iPSCs from a differentiated cell such as a fibroblast. Alternatively, the concept of “direct reprogramming” refers to a switch in phenotype from one lineage to another without going through a multipotent or pluripotential intermediate state. This usually involves genetic manipulation (e.g., fibroblast to neuronal cell or liver cell) by expression of a few transcription factors or may occur in injury, for example conversion of pancreatic exocrine cells to hepatocytes in copper deficiency. The ability of Scgb1a1+ club cells to give rise to type 2 alveolar epithelial cells after certain kinds of lung injury may be another example of reprogramming in response to injury.

Dedifferentiation: Change in phenotype of a cell so that it expresses fewer differentiation markers and changes in function, such as an increase in differentiation potential (e.g., reversion of a differentiated secretory cell to a basal stem cell in the tracheal epithelium and blastema formation during tissue regeneration in amphibians). In most respects, this is synonymous with reprogramming.

Transdifferentiation: The process by which a single differentiated somatic cell acquires the stable phenotype of a differentiated cell of a different lineage. The classic example is the differentiation of a pigmented epithelial cell of the amphibian iris (neurectoderm) to a lens cell (ectoderm). May involve transition through a dedifferentiated intermediate, usually but not necessarily with cell proliferation. The distinction between transdifferentiation and reprogramming may be semantic.

Epithelial–mesenchymal transition: A developmental process in which epithelial cells acquire phenotypic and functional attributes of mesenchymal-origin cells, usually fibroblastic cells. Whether this process occurs in adult lungs (or other adult tissues) remains controversial. In cancer biology, epithelial cells can change shape, polarity, and migratory capacity characteristic of other cell phenotypes, but whether they have undergone a full lineage transition remains unclear.

Plasticity: Ability of a cell to change its phenotype through the process of dedifferentiation, reprogramming, or transdifferentiation. Mature differentiated cells may be more difficult to dedifferentiate into an iPSC than are immature cells or tissue stem cells. Another use of the term plasticity is to describe normally adaptive changes in cell phenotype as they adapt to different environmental conditions.

Embryonic stem cells (ESCs): Cell lines developed from the inner cell mass of a blastocyst stage embryo. ESCs have the capacity for self-renewal and are pluripotent, having the ability to differentiate into cells of all three germ layers and all adult cell types. Mouse (but not human) ESCs cannot form extraembryonic tissue such as trophectoderm.

Adult stem cell: Cells from adult tissues, such as bone marrow, intestine, nervous tissue, and epidermis, that have the capacity for long-term self-renewal and differentiation into cell types specific to the tissue in which they reside. These cells can also regenerate the tissue after transplantation or injury. In general, adult stem cells are multipotent, having the capacity to differentiate into several different mature cell types of the parent tissue. The differentiation potential of a single adult stem cell may change after transplantation to a new environment or in response to local injury/inflammation or after culture. For example, MSCs from adipose tissue can give rise to smooth muscle, cartilage, or bone when cultured under different conditions and/or in response to specific signaling factors. Although easy to track in in vitro culture systems using isolated cells, demonstrating this change in potential in vivo requires single cell lineage tracing.

Induced pluripotent stem cell (iPSC): Reprogrammed somatic cells that have undergone a resetting of their differentiated epigenetic states into a state reminiscent of embryonic stem cells after the expression of reprogramming molecules, such as the transcription factors Oct 3/4, Sox2, c-Myc, and Klf4. iPSCs are similar to ESCs in morphology, proliferation potential, pluripotent differentiation repertoire, and global transcriptomic/epigenomic profiles. In vivo implantation of iPSCs results in formation of tissues from all three embryonic germ layers. iPSCs have been generated from both mouse and human cells.

Progenitor cell: A general term traditionally used to describe any relatively immature cell that has the capacity to proliferate, giving rise to mature postmitotic cells within a given tissue. More recent evidence suggests that differentiated epithelial cells in the lung can act as progenitors under certain conditions. Unlike stem cells, progenitor cells are generally believed to have limited or no self-renewal capacity and may undergo senescence after multiple cell doublings. The literature continues to blur distinctions between uses of the terms “stem” and “progenitor.”

Transit-amplifying cell: The progeny of a tissue stem cell that retains a relatively undifferentiated character, although more differentiated than the parent stem cell, and demonstrates a finite capacity for proliferation. One recognized function of transit-amplifying cells is the generation of a sufficient number of specialized progeny for tissue maintenance or repair. There may be other as-yet-unknown functions.

Obligate progenitor cell: A cell that loses its ability to proliferate once it commits to a differentiation pathway. Intestinal transit amplifying cells are a traditional example. However, it has recently been demonstrated that some intestinal transit amplifying cells can give rise to Lgr5+ intestinal stem cells after ablation of the resident Lgr5+ population.

Facultative progenitor cell: A cell that exhibits differentiated features when in the quiescent state yet has the capacity to proliferate for normal tissue maintenance and in response to injury. Bronchiolar club cells are an example of this cell type. However, it is becoming apparent that there are likely multiple populations of club cells, not all of which may function in this respect.

Classical stem cell hierarchy: A stem cell hierarchy in which the adult tissue stem cell actively participates in normal tissue maintenance and gives rise to transit-amplifying progenitor population. Within this type of hierarchy, renewal potential resides in cells at the top of the hierarchy (i.e., the stem and transit-amplifying cell), and cells at each successive stage of differentiation become less potent.

Nonclassical stem cell hierarchy: A stem cell hierarchy in which the adult tissue stem cell does not typically participate in normal tissue maintenance but can be activated to participate in repair after progenitor cell depletion. A related concept is that of population asymmetry or neutral drift, in which there is no dedicated slow-cycling stem cell but rather a pool of equipotent cells that can give rise to clones of differentiated progeny. This has been shown for intestine, interfollicular epidermis, testis, and human airway basal cells.

Rapidly renewing tissue: Tissue in which homeostasis is dependent on maintenance of an active mitotic compartment. Rapid turnover of differentiated cell types requires continuous proliferation of stem and/or transit-amplifying cells. A prototypical rapidly renewing tissue is the intestinal epithelium.

Slowly renewing tissue: Tissues in which the steady state mitotic index is low. Specialized cell types are long lived and some, perhaps all, of these cells, the facultative progenitor cells, retain the ability to enter the cell cycle in response to injury or changes in the microenvironment. The relative stability of the differentiated cell pool is paralleled by infrequent proliferation of stem and progenitor cells. The lung is an example of a slowly renewing tissue.

Hematopoietic stem cell: Cell that has the capacity for self-renewal and whose progeny differentiate into all of the different blood cell lineages, including mature leukocytes, erythrocytes, and platelets.

Endothelial progenitor cell: This term has been replaced with the following two categories of cells.

Proangiogenic hematopoietic cell: Bone marrow–derived hematopoietic cells that display the ability to functionally augment vascular repair and regeneration principally via paracrine mechanisms. Most evidence indicates that the recruited proangiogenic hematopoietic cells circulate to sites of tissue injury and facilitate resident vascular endothelial cell recruitment to form new vessels but lack direct vessel-forming ability. In general, most prior uses of the term endothelial progenitor cell have now been demonstrated to be more appropriately described as effects emanating from proangiogenic hematopoietic cells.

Endothelial colony–forming cell: Rare circulating blood cells that display the ability to adhere to tissue culture plastic or matrix proteins in vitro, display robust clonal proliferative potential, and generation of cells with endothelial lineage gene expression and in vivo blood vessel forming potential when implanted in a variety of natural or synthetic scaffolds. Endothelial colony–forming cells have also been termed blood or late outgrowth endothelial cells and, in some cases, have also been referred to as endothelial progenitor cells.

Mesenchymal stromal (stem) cells: Cells of stromal origin that can self-renew and give rise to progeny that have the ability to differentiate into a variety of cell lineages. Initially described in a population of bone marrow stromal cells, they were first described as fibroblastic colony-forming units, subsequently as marrow stromal cells, then as mesenchymal stem cells, and most recently as multipotent mesenchymal stromal cells or MSCs. MSCs have now been isolated from a wide variety of tissues, including umbilical cord blood, Wharton’s jelly, placenta, adipose tissue, and lung. The Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy has published the minimal criteria for defining (human) MSCs in 2006 (116). However, this definition is being reinvigorated as it has become clear that the functional attributes of MSCs, (i.e., potency in any given application), in combination with cell surface markers, differentiation capacity, source, or culture conditions, will provide a more relevant framework for study and potential therapeutic use of MSCs (38).

Fibrocyte: A cell in the subset of circulating leukocytes that produce collagen and home to sites of inflammation. The identity and phenotypic characterization of circulating fibrocytes is more firmly established than that for EPCs. However, whether fibrocytes originate from bone marrow lymphoid or myeloid progenitors remains unclear. These cells express the cell surface markers CD34, CD45, CD13, and MHC II and also express type 1 collagen and fibronectin.

Airway basal stem cells: Cells present within the pseudostratified airway epithelium that are rich in hemidesmosomal connections that anchor the epithelium to the basement membrane. These cells are characterized by the variable expression of p63 and cytokeratins (K)5 and 14. There are more K5-positive basal cells in the airway than p63-positive cells. Not all K5-positive cells express p63 at steady state. K14 is expressed in self-renewing basal cells and is only present in rare basal cells at steady state. In the pseudostratified proximal airway epithelium, basal cells function as stem cells that give rise to ciliated and secretory cells. Recently, cells with some features of basal cells were described in the distal lung. The extent of the molecular and function similarity of these cells to basal cells of the upper airways is not clear.

Bronchiolar stem cell: A term applied to a population of naphthalene-resistant Scgb1a1lo, Scb3a2hi expressing cells that localize to neuroepithelial bodies and the bronchoalveolar duct junction of the rodent lung. These cells proliferate infrequently in the steady state but increase their proliferative rate after depletion of mature club cells by naphthalene. Lineage tracing studies indicate that these cells have the ability to self-renew and to give rise to Scgb1a1 club cells and ciliated cells after injury. Apart from naphthalene resistance, there is no evidence that these cells have a higher capacity for functioning as facultative progenitors than Scgb1a1+ club cells. Human correlates have not yet been identified.

Bronchioalveolar stem cell (BASC): A term applied to a rare population of cells (<1 per terminal bronchiole) located at the bronchoalveolar duct junction in the mouse lung identified in vivo by dual labeling with Scgb1a1 and Sftpc and by resistance to destruction with naphthalene or bleomycin. In culture, dual-positive cells can be enriched by FACS by selecting for cells that also express Sca1 and CD24. However, these markers can also be expressed on other cells. The BASCs can self-renew and give rise to progeny that express either alveolar epithelial lineage markers such as Sftpc, or aquaporin 5, or progeny that express airway epithelial lineage markers such as Scgb1a1. Currently, it is unknown if BASCs or club cells have any true phenotypic or functional distinction, as there is no evidence that the dual-positive cells are any more likely than single-positive Scgb1a1 club cell abilities to give rise to type 2 and type 1 cells either in culture or in vivo after injury. Notably, there are currently no known BASC-specific markers to distinguish them from club cells in vivo. However, in three-dimensional cocultures, single BASCs are multipotent, with the ability to produce alveolar or airway lineages. Human correlates have not yet been identified.

Definition of abbreviations: FACS = fluorescence-activated cell sorter; iPSC = induced pluripotent stem cell; MHC = major histocompatibility complex; MSC = mesenchymal stromal cell.

Modified by permission from Reference 1. The authors gratefully acknowledge input and discussion toward updating of this table from the following individuals: Christina Barkauskas, Brian Davis, Massimo Dominici, John Engelhardt, Amy Firth, Brigitte Gomperts, Erica Herzog, Carla Kim, Darrell Kotton, Laertis Ikonomou, Luis Ortiz, Darwin Prockop, Susan Reynolds, Duncan Stewart, Barry Stripp, and Mervin Yoder.