Towards a classification of stem cells Lucie Laplane, Eric Solary To cite this version: Lucie Laplane, Eric Solary. Towards a classification of stem cells. eLife, eLife Sciences Publication, 2019, 8, 10.7554/eLife.46563. hal-02269662 HAL Id: hal-02269662 https://hal.archives-ouvertes.fr/hal-02269662 Submitted on 23 Aug 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. FEATURE ARTICLE PHILOSOPHY OF BIOLOGY Towards a classification of stem cells Abstract The characteristic properties of stem cells – notably their ability to self-renew and to differentiate – have meant that they have traditionally been viewed as distinct from most other types of cells. However, recent research has blurred the line between stem cells and other cells by showing that the former display a range of behaviors in different tissues and at different stages of development. Here, we use the tools of metaphysics to describe a classification scheme for stem cells, and to highlight what their inherent diversity means for cancer treatment. LUCIE LAPLANE AND ERIC SOLARY n certain multicellular organisms, stem cells with renewing the lining of the bowel I can serve as reservoir of cells to produce, (Tetteh et al., 2016). Such flexibility suggested maintain, repair or even regenerate many that stemness might not be restricted to a pre- tissues. Similarly, in cancer, a distinct fraction of defined population of cells and prompted some cells, called cancer stem cells, may fuel the biologists to question what stem cells really entire tumor as the disease emerges and pro- were. gresses (Batlle and Clevers, 2017). How to Traditional views of stem cells arose from define, isolate or characterize both healthy and studies of the hematopoietic tissue in the bone cancer stem cells is a subject of much debate. marrow, where blood cells originate in adults. Here, we provide a philosophical analysis of However, in the late 1970s, Ray Schofield sug- ’stemness’ – the defining property of stem cells gested that stemness actually relies on the inter- – arguing that this approach may shed new light action of hematopoietic stem cells (the cells that on the nature of normal and malignant stem give rise to other blood cells) with the microenvi- cells. We show that, depending on the circum- ronment in which they reside (Schofield, 1978). stances, stemness may belong to one out of four Although long denied, the importance of this distinct properties and discuss how this may ’niche’ is now increasingly accepted: hematopoi- influence therapeutic strategies in the oncology etic stem cells cannot be understood out of their field. context, which may account for the difficulties in maintaining them in culture. Finally, new technologies, such as lineage One size does not fit all tracing, have further questioned the boundaries Stem cells have been described as a discrete of the stem cell category, as studies have shown population of cells sitting at the apex of a hierar- that not every individual hematopoietic stem cell chy of irreversible cell differentiation. This view appears to be multipotent (discussed in has had an impact on the way in which stem cell Haas et al., 2018). These analyses highlighted research is performed by, for example, encour- that non-hematopoietic stem cells, called multi- Copyright Laplane and Solary. aging the idea that specific markers may help to potent progenitors, could unexpectedly main- This article is distributed under the distinguish and sort stem cells. However, tain the production of hematopoietic cells over terms of the Creative Commons researchers discovered that certain tissues an extended period of time (Sun et al., 2014). Attribution License, which permits showed much more plasticity in cell fate than These are only a few of the examples that illus- unrestricted use and redistribution provided that the original author and anticipated. For example, it appeared that intes- trate the potential diversity of these cells, which source are credited. tinal cells could replace the stem cells tasked has resulted in two opposite views of what a Laplane and Solary. eLife 2019;8:e46563. DOI: https://doi.org/10.7554/eLife.46563 1 of 5 Feature article Philosophy of Biology Towards a classification of stem cells Researchers discovered that certain replaced by differentiated cells that migrate back to the stem cell niche, where they reac- tissues showed much more plasticity quire stemness (e.g. Brawley and Matunis, in cell fate than anticipated 2004). Stemness could also be a relational prop- erty in some cancers: recent research in a mouse model of colon cancer has revealed that after cancer stem cells had been eliminated, some remaining cancer cells regained stemness in the stem cell is: it can either be an entity, a discrete primary tumor but not in liver metastases, sug- population of cells with stable properties, or it gesting that a specific niche is required for the can be a cell state, a property that is acquired in acquisition of stemness (de Sousa e Melo et al., a specific context (e.g. Clevers and Watt, 2018; 2017). Zipori, 2004). Finally, stemness can be a ’systemic’ prop- erty, defined as an extrinsic characteristic that is provided and maintained by the system. For Some order in the stemness mess example, in the Matrix movie, every time the Philosophy, and more specifically metaphysics, main antagonist Agent Smith is killed, the sys- has a long tradition of characterizing and distin- tem transforms any human to incarnate the guishing different types of properties for the agent. Likewise, stemness is a systemic property objects or systems around us. We recently used when non-stem cells acquire stemness features this tradition to characterize stemness and our in the absence of a specific environment, which analysis led us to the conclusion that four types may be the case in cancer. For example, some of properties may exist under the guise of stem- differentiated cells from breast cancer cell lines ness (Laplane, 2016; Laplane and Solary, can become cancer stem cells again when cul- 2017). tured in vitro (Gupta et al., 2011). This suggests Stemness can be a ’categorical’ property, that stemness can be reacquired without a spe- that is, an intrinsic feature that is independent of cific niche, with regulation taking place at the any interaction with surrounding entities, such as system level – here, the cancer cell population. the atomic mass of an element. It was initially Stemness therefore encompasses distinct assumed that all stem cells belong to this class, properties, depending on the tissue and con- but, as discussed below, it might only apply to text. Which category a stem cell population certain cancers. belongs to depends on two questions that can Alternatively, stemness can be a ’disposi- be addressed experimentally: first, can stemness tional’ property, which is also an intrinsic feature, be acquired by non-stem cells of that tissue? but one that only manifests upon interaction And second, is the niche mandatory for the with external stimuli. For example, a fragile item acquisition of stemness, the expression only breaks on impact. Current knowledge sug- of stemness, or both? gests that healthy hematopoietic stem cells fall under this category. Although stemness is hard- wired in these cells, it tightly depends on the Stemness in cancer bone marrow niche. In a malignant context, In oncology, the cancer stem cell model presup- however, hematopoietic progenitor cells can poses that cancers maintain an organization sim- gain stemness as they transform into malignant ilar to that of healthy tissues, with a pool of cells, questioning the maintenance of stemness malignant stem cells acting as the main reservoir as a dispositional property. for the production of every other cell of the Stemness can also be a ’relational’ property tumor. These cells may be generated by the that relies on the interaction between entities. transformation of typical stem cells in the tissue For example, body weight depends on gravity, of origin. The relationship between the rate of and differs on the Earth and the Moon. Unlike stem cell division and the risk of malignant trans- the dispositional property, a relational property formation in a given tissue has led to much con- is not hardwired in a predetermined pool of troversy in recent years (Tomasetti et al., 2017; cells, such as germline stem cells (which give rise Tomasetti and Vogelstein, 2015). Alternatively, to egg and sperm cells). When these stem cells cancer stem cells may emerge from non-stem are removed in fruit flies and mice, they are cells endowed with stemness abilities thanks to Laplane and Solary. eLife 2019;8:e46563. DOI: https://doi.org/10.7554/eLife.46563 2 of 5 Feature article Philosophy of Biology Towards a classification of stem cells result in stemness acquisition, squamous cell car- cinomas may fall into two categories. In the Stemness encompasses distinct absence of transition, stemness would best described as a dispositional property: intrinsic to properties, depending on the tissue the cells, but only revealed in the right context. and context However, in the presence of frequent transitions, stemness would become a relational property – extrinsic and conditional on epithelial-to-mesen- chymal transitions. Taken together, cancer occurrence and pro- genetic and epigenetic alterations. Similarities gression could be associated with changes in and dissimilarities between normal stem cells the nature of stemness. It remains to be seen and cancer stem cells open three questions.