A SYSTEMATIC REAPPRAISAL VIA THE GENOSTEM EXPERIENCE

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Concerning bone marrow MSC biology, work performed in Genostem has has helped solve three major problems. We now know 1) where the native cells are located (on the abluminal side of endothelial cells of sinuses) and how to select them, 2) that stromal cells forming the niche of hematopoietic stem cells and bone marrow MSCs are the same entity, thus resolving a long-standing issue, and  3)  that clonal highly proliferative culture-amplified cells are bona fide stem cells since sharing with the other paradigmal adult stem cells, the hematopoietic stem cells, two major properties, that of self-renewal and that of multipotential priming. Many issues remain to be solved. Are MSCs also primed to the tenogenic lineage ? Is it possible to describe for the MSC system a hierarchy among precursors that would discriminate between self-renewing multipotential MSCs and progenitors/transit amplifying cells devoid of self-renewal capacity, and more restricted in their differentiation ability (note that such ”classical” model for stem cell differentiation in other systems is presently under much debate (32, 33)) ? Is the self-renewal capacity of MSCs comparable to that of hematopoietic stem cells (sequential transplantations would solve this problem) ? Would cross-inhibitory loops between transcription factors account for multipotential lineage priming in MSCs, as suggested for hematopoietic or embryonic stem cell lineage priming (34) ? Does the reprogrammation of MSCs into non primed lineages (35, 36) implies reversion to pluripotent cell stage  as described for skin fibroblasts (37), or is true transdifferentiation possible (38)? What is the influence of the surrounding matrix and biomechanical stress on lineage priming and programming/reprogramming of MSCs (39) ?

Genostem identified and developed a set of new biomaterials and scaffolds that showed adequate performance in vivo for the repair of bone and cartilage. The cohort of biomaterials and scaffolds proposed by Genostem continues being developed towards pre-clinical testing for the repair of connective tissues aiming at reaching the clinical testing stage.

Concerning bone repair, work performed in Genostem led to identify novel genes and factors that promote MSC osteogenic differentiation and osteogenesis in vitro and in vivo. Future studies, now ongoing, will determine whether some of these genes or factors can be used to promote bone repair in preclinical settings. Ongoing studies are also aimed at identifying other genes and proteins that are upregulated during MSC osteogenic differentiation and can be used to promote the osteogenic and bone repair processes.

Concerning cartilage repair, work performed in Genostem opens perspectives for the cell therapy of disorders including cartilage defect and cartilage damage related to arthritis/osteoarthitis. However, results in the long term evaluating integration of the newly formed tissue with the native cartilage need to be obtained before large application in clinical practice can be envisioned.

Concerning tendon repair, identification of the signalling molecules implicated in tenogenesis has been a major step forward. Future studies will determine how this newly-acquired knowledge may be applied to preclinical models using human bone marrow MSCs, before considering clinical application in cases of tendon rupture.

Whatever the site of repair, the mechanisms of repair still need to be elucidated. A traditional view would be that the transplanted donor MSCs migrate to the injured site where they proliferate and differentiate into appropriate cells (osteoblasts, chondrocytes or tenocytes pending on the injured tissue). An alternative view would be that MSCs provide growth factors helping in situ host MSCs to proliferate and differentiate. Such trophic effect has been recently shown in an animal model of fracture healing (40) and is suggested to be the major mechanism to explain the beneficial role of MSC administration in non-orthopedic-related disorders such as vascular repair (41).

A last important issue is whether bone marrow MSCs are identical to other connective-tissue forming cells not found in bone marrow (adipose tissue, umbilical cord vessel, Wharton’s jelly, placenta…). Many authors suggest this to be the case, the major arguments being the similarity of phenotype and of differentiation capacity (into osteoblasts, chondrocytes, adipocytes and even myocytes) between cells derived from bone marrow and other tissues (42). Data from Genostem contradict this hypothesis stressing that bone marrow MSCs present unique properties : specific expression of certain membrane antigens, unique ability to form bone and transfer the hematopoietic microenvironment in vivo after transplantation to ectopic sites, specific transcriptomic profile… (5-7, 43). Further studies should more closely discriminate the connective-tissue stem cell types with regard to their tissue of origin.