A SYSTEMATIC REAPPRAISAL VIA THE GENOSTEM EXPERIENCE
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.
Post Comment
No comments