COMMENTARY

Cytotherapy, 2010; 12: 438–439

Getting beneath the skin to understand MSC complexity

MASSIMO DOMINICI1 & EDWIN M. HORWITZ2

1Laboratory of Cell Biology and Advanced Cancer Therapy, Division of Oncology, University of Modena and Reggio Emilia, 2Division of Oncology/Blood and Marrow Transplantation, The Children’s Hospital of Philadelphia and The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 USA

Correspondence: Dr. Massimo Dominici, MD, Laboratory of Cell Biology and Advanced Cancer Therapies, Dpt. Oncology, Hematology and Respiratory Diseases, University of Modena and Reggio Emilia, Via del Pozzo, 71, ZIP: 41100, Modena, Italy. Ph 0039-059-422-2858/4019; Fax 0039-059-422-3341, E-mail: massimo.dominici@unimore.it

Since their initial description, mesenchymal progeni-tors have exhibited two general functions: to directly generate tissue by differentiation and to support the survival and proliferation of other cells/tissues by secreting cytokines or growth factors. This dual-function paradigm was represented in the original description of mesenchymal progenitors, now des-ignated as marrow stromal cells (MSC), by their capacity to give rise to bone cells and to support hematopoiesis in vitro (1–3).

Since the earliest studies of MSCs, hundreds of reports have been published describing marrow MSC differentiation into mesodermal, ectodermal and endodermal lineages suggesting a vast regen-erative potential and properties of “stemness” (4,5). While the early in vitro experience created much excitement, the subsequent in vivo data, based on systemically infused cells, was inconsistent with those early fi ndings (6). More recently, many studies indi-cate that tissues other than marrow may comprise important sources of mesenchymal progenitors which can be utilized in the context of cellular therapies. These recent fi ndings have prompted scientists to explore whether these tissue-specifi c MSC may be better suited for specifi c applications in regenera-tive medicine (7). Despite much promising data and many interesting hypotheses, several issues have yet to be clarifi ed.

In this issue of Cytotherapy, two papers explore the dual function of MSC focusing on the charac-terization of the cellular events in the regeneration of bone and brain.

To understand the behaviour of MSC during differ-entiation, Giusta et al. (8) considered adipose-derived mesenchymal cells induced to generate bone-forming cells. These authors used a proteomic analysis of the

ISSN 1465-3249 print/ISSN 1477-2566 online © 2010 Informa UK Ltd. (InfDOI: 10.3109/14653249.2010.499712

progenitors to follow cellular commitment at the pro-tein level. Coupling FACS and RT-PCR analyses with protein expression at baseline, and after bone induc-tion at 14 and 28 days, the authors selected 51 dif-ferentially expressed proteins. Most intriguing, only 7 proteins were found to signifi cantly vary between the baseline cells and the bone-induced MSC after 14 days. These fi ndings represent an example of using a relatively simple experimental model to narrow pool of selected markers of tissue commitment to investigate unexplored aspects of cellular differentiation.

While it is well known that human MSC retain a stromal/supportive function for hematopoietic stem cells, Habisch HJ et al. (9) provide novel data dem-onstrating that marrow MSC may be also associated with a supportive function for neural stem cells. These authors demonstrate the ability of MSC to differentiate along the neuroectodermal lineage and show how this event is associated with a stromal function for neural progenitors. Thus, these fi ndings couple the regenera-tive roles of differentiation with a supportive function. The data are supported by an extensive analysis of growth factors, which produced by neuro-committed MSC, could favour NSC survival and proliferation. In particular, real-time PCR, gene array and ELISA revealed that neuro-differentiated MSC increase their levels of hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and amphiregulin; all factors known to be involved in increasing neural stem cell proliferation. Within the limits of a xeno-genic model, the study also reveals that the inter-action with neuroectodermal differentiated human MSC protect rodent NSC from a damage induced by a neurotoxin. These data also provide promising insights into the potential of MSC as a cellular vehi-cle to regenerate neurodegenerative diseases, since

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Commentary 439

the in vitro differentiation of mesodermal derived cells into ectodermal derived neurons has been previously questioned (10).

Collectively, these two papers suggest a strategy refl ecting the necessity “to go inside the cells” for a better understanding of the events which trigger and maintain MSC differentiation and their role in regenerating tissues. The award-winning movie “Being John Malkovich”, where a couple fi nds a way to transfer people into the famous actor’s mind to experience how the actor was feeling, is Hollywood’s version of this strategy. The movie slogan, “Ever wanted to be someone else?” refl ects one of the cru-cial questions in MSC biology. What makes mesen-chymal stromal cells “want to differentiate into some other cell?” Investigators are assured in fi nding that MSC are CD105+, CD90+ and CD45- or that bone induced MSC are red after Alizarin stain but this, in a near future, may not be enough. We all should aim for an “into-cell” screening which combines well know proliferation and differentiation protocols with epigenomics, genomics and proteomics. These high-throughput analyses combined and performed either in vitro or in vivo at baseline and after differentia-tion, could more specifi cally provide insights on the complex events which are taking place during MSC commitment. Such studies may facilitate the identi-fi cation of early surrogate markers of differentiation allowing a true understanding of MSC potentials for optimized therapeutic approaches. In the very end we may even understand what it’s like “being MSC.”

Declaration of interest: The author reports no confl icts of interest. The author alone is responsible for the content and writing of the paper.

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