Murray and Péault BMC Biology (2015) 13:99 DOI 10.1186/s12915-015-0212-7 QUESTION AND ANSWER Open Access Q&A: Mesenchymal stem cells — where do they come from and is it important? Iain R. Murray1 and Bruno Péault1,2* in vitro as well as in vivo upon re-transplantation [2–4]. Abstract In light of their capacity to differentiate into bone, fat, Mesenchymal stem — or stromal — cells (MSCs) have cartilage and muscle in culture and an emerging link to been administered in hundreds of clinical trials for the embryonic development of various mesenchymal tis- multiple indications, making them some of the most sues, the term “mesenchymal stem cell” was coined in commonly used selected regenerative cells. 1991 by Arnold Caplan to describe these cells [5]. Cells Paradoxically, MSCs have also long remained the least with similar characteristics have since been found to characterized stem cells regarding native identity and emerge from cultures of virtually all adult and fetal organs natural function, being isolated retrospectively in tested [6]. Observation of these cells in culture led to a long-term culture. Recent years have seen progress in definition of MSCs by the International Society of Cell our understanding of the natural history of these cells, Therapy (ISCT) that included a propensity to adhere to la- and candidate native MSCs have been identified boratory culture plastic and the capacity to differentiate within fetal and adult organs. Beyond basic into at least bone, cartilage and fat [7]. MSCs were subse- knowledge, deciphering the biology of innate MSCs quently found to have a characteristic, although not spe- may have important positive consequences for the cific, set of surface markers, with additional functions therapeutic use of these cells. including the secretion of immunomodulatory factors and support, albeit limited, of hematopoiesis. This body of work suggested that MSCs natively re- What are mesenchymal stem cells, and how are sided in all the tissues from which they were isolated; they conventionally isolated? however, their exact location (whether in the stroma or, Mesenchymal stem cells (MSCs) are multipotent stromal for instance, in blood vessels) was still not known. An cells that can differentiate into a variety of lineages, in- improved understanding of the native identity and biol- cluding osteocytes, adipocytes and chondrocytes. This ogy of these cells has recently been sought. differentiation capacity, in addition to their release of trophic factors and immunomodulatory properties, holds great promise for cell therapies and tissue engineering. Is it important to understand the native origin of MSCs are not a new phenomenon. In the late nineteenth MSCs? century the German biologist Cohnheim hypothesized Yes, a complete understanding of the native origin of that fibroblastic cells derived from bone marrow were MSCs will allow their therapeutic potential to be fully involved in wound healing throughout the body [1]. In exploited. The documented multipotency, immunomod- the 1970s Alexander Friedenstein, who is generally cred- ulatory and trophic effects of MSCs sparked great excite- ited with the discovery of MSCs, described a population ment and enthusiasm to explore the use of MSCs as of plastic-adherent cells that emerged from long-term progenitors in tissue engineering to replace damaged tis- cultures of bone marrow and other blood-forming or- sues of mesodermal and possibly other germ line origins, gans, and that he showed to have colony forming to promote regeneration, and to treat immune-mediated capacity and osteogenic differentiation characteristics disease [8]. As such, the number of clinical trials using MSCs has been rising almost exponentially since 2004. * Correspondence: [email protected] However, with the “gold rush” to use MSCs in the clin- 1 BHF Centre for Vascular Regeneration, Scottish Centre for Regenerative ical setting, the question of what MSCs naturally do in Medicine, University of Edinburgh, Edinburgh, UK 2Orthopedic Hospital Research Center and Broad Stem Cell Center, David bone marrow and other tissues, and what intrinsic roles Geffen School of Medicine, University of California, Los Angeles, CA, USA these populations may play in vivo, beyond how their © 2015 Murray and Péault. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Murray and Péault BMC Biology (2015) 13:99 Page 2 of 6 functional traits might be harnessed in response to not necessarily associated with capillaries and microves- culture-related artificial cues or settings, were not sels. A population of progenitors located in the outmost understood. Cells were being used for therapeutic pur- layer of larger arteries and veins, the tunica adventitia, poses without a true understanding of their native ori- has also been identified as a source of bona fide MSCs gin or function. An improved understanding of their [10]. Adventitial progenitors are phenotypically and ana- location and function within tissues would not only sat- tomically distinct from pericytes. However, like pericytes, isfy scientific curiosity but also facilitate potential thera- adventitial cells natively express MSC markers. In this peutic targeting of these cells. regard, pericytes and adventitial cells have been collect- ively termed perivascular stem cells or PSCs (Fig. 1). Are MSCs artifacts of culture, or do identical cells Although experimental evidence points to a perivascu- natively reside in tissues, and if so, where? lar origin of culture-selected MSCs, the possibility that The answer to that remained obscure for many years. As non-vascular cells in some tissues can yield MSCs in described above, MSCs have historically been isolated in culture cannot be excluded. In support of this it has re- culture, being selected from total cell suspensions based cently been observed that a subset of osteogenic progen- on their ability to adhere and proliferate for several itors that exhibit MSC potential reside within cranial weeks of primary cultivation. At difference with, for in- sutures but do not appear to be associated with blood stance, hematopoietic stem cells, which were initially vessels [11]. However, it remains to be demonstrated identified within mixed cell populations then increas- that such progenitor cells are not affiliated with perivas- ingly enriched with markers and eventually purified to cular cells that emerged earlier in development, but homogeneity from the bone marrow, MSCs remained eventually migrated away from the vascular niche. for decades retrospectively isolated cells of unknown na- tive identity, tissue distribution, frequency, or natural How do native MSCs support tissue regeneration? function in vivo [6]. Typically, the MSC description pro- Although the multipotent, immunomodulatory and vided by ISCT in 2006 — that is, 40 years after Frieden- trophic effects of MSCs demonstrated in culture hold stein’s original observations — still relied exclusively on great promise for cell therapy [12], whether these MSCs markers defined in culture, giving no clue as to the in- also play a natural role in tissue regeneration in vivo is nate character of these cells in vivo. With these cells not yet fully established. The discovery that pericytes having been only identified in a process requiring long- represent innate MSCs has greatly facilitated our under- term culture and a definition based entirely on in vitro standing of the native roles of MSCs, as these cells can characteristics, it has been proposed by some that MSCs now be studied in vivo and their fates explored through merely represent an artifact of culture. This is supported lineage tracing using established pericyte markers [13]. by a body of literature confirming that cell phenotypes Recent publications have already documented the direct are altered by exposure to culture products and adher- involvement of perivascular progenitor cells in the devel- ence to stiff culture matrices. However, a number of opment and/or regeneration of white adipocytes [14], large-scale studies of multiple human tissues have identi- skeletal muscle [15], follicular dendritic cells [16] and fied vascular pericytes (which ensheathe capillaries and dental pulp [13]. Altogether, these observations suggest microvessels in all tissues) by immunohistochemistry, the presence in the adult of regenerative cells associated and then purified those to homogeneity by flow cytometry with all blood vessels, hence broadly disseminated [9]. Cultured pericytes, notwithstanding tissue of origin, throughout the organism. Intriguingly, pericyte contribu- turned out to be indistinguishable from conventional tion to musculoskeletal tissue development and regener- MSCs in terms of adherence, morphology, phenotype, ation is not absolute and varies with anatomical location. proliferation rate, and developmental potential. Import- For example, the contribution of pericytes to myofibers antly, native expression of the MSC markers CD73, CD90, varies among different muscles, ranging from