What are Mesenchymal Stem Cells ?

 

Regeneration takes place in the body at one time point or the other throughout life.

 

Bone, cartilage, and tendons (the key components of the structure and articulation in the body) have a limited capacity for self repair and, after traumatic injury or disease, the regenerative power of adult tissue is often not sufficient. When organs or tissues are irreparably damaged, they may be replaced by an artificial device or donor organ. However, the number of available donor organs is critically limited.

 

Generation of tissue-engineered replacement organs by extracting stem cells from the patient, grow and modify in the clinic and then re-introduce represents an ideal source for corrective treatment.

 

1. Stem cells are taken from a patient's organ

2. they proliferare and differentiate into a desired type of cell,

3. they are reintroduced into the same patient to reconstitute damaged organ

4. by disease or accident

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MSCs are multipotential stem cells differentiating into connective tissue forming cells and providing the critical substrate (niche) for other stem cells, primarily HSCs. MSCs via the production of their own extracellular matrix may provide for their own niche.

 

MSCs constitute a heteregenous population. Colonies differ widely in their growth potential with some clones growing extensively for more than 30 population doublings.

 

This means that one MSC can give rise to over one billion progeny!!

 

MSCs are also heterogenous in their differentiation potential. For instance, in one study, some clones are tri-potential (adipocytic, osteoblastic and chondrogenic) while most are only bi- or uni-potential. Differentiation pathways have also been demonstrated by experiments in animals or by means of clinical trials. Marrow MSCs from normal mice injected in mice with osteogenesisimperfecta were detected in bone marrow, bone, cartilage and corrected, to a certain extent, the deficit incollagen I.  Improvement in the clinical condition has been reported in  patients with osteogenesis imperfecta graftedwith MSCs. Implantation of bone marrow concentrates in foci of pseudarthrosis has allowed accelerated bone consolidation. Similarly, injection of bone marrow in cancer patients where a bone resection had been performed allowed bone reconstitution in most cases. A recent clinical study has shown that human marrow stromal cells implanted locally accelerated  the healing of majorbone deficits.

 

This set of experimental and clinical results indicate the therapeutic potential of MSCs for the repair of different tissues. However, the study of the differentiation potential is complex because of the remarkable plasticity of the mesenchymal lineages, that is the possible shift in differentiation from one lineage to the other (for example by changing culture conditions). Plasticity is amplified in cell clones where a switch from the fat to the bone lineage and from cartilage to bone. Therefore, the MSC system appears to be distinct from other classical stem cell systems wherein the existence of a stem cell compartment is required by the irreversible differentiation of the progeny.

 

Recently Multipotent Adult Progenitor Cells (MAPCs) have been described. These non hematopoietic (CD45-negative) cells are isolated from the marrow of mice, rats and humans, cultured for a few days in a medium containing low percentage serum with specific growth factors. MAPCs cangive rise to endothelial cells and, more surprisingly, to neuroectodermal(neurons, astrocytes and oligodendrocytes) and endodermal (hepatocytes) derivatives. Whether MAPCs are a subpopulation of MSCs with remarkable plasticity, as suggested by data showing a possible neural or hepatocytic differentiation of MSCs/stromal cells, or a distinct adult stem cell population maintaining the differentiation potential of embryonic stem cells, remains an open question.

 

In GENOSTEM we will focus on the mesodermic differentiation pathways which do not require to set up the 2-step procedure described for MAPCs. GENOSTEM will consider the different problems that should be solved to successfully engineer tissues from MSCs to develop clinical trials using autologous MSCs in bone, cartilage,and connective tissue disorders, in partnership with companies and regulatory bodies for the scale up

of safe and clinically applicable procedures.

MSCs are the multipotential progenitors that give rise to skeletal cells (bone and tendon), vascular smooth muscle cells (VSMCs),  muscle (skeletal and cardiac muscle), adipocytes (fat tissue) and hematopoietic(blood)-supportive stromal cells. MSCs are found in multiple connective tissues, in adult bone marrow, skeletal muscles and fat pads .The wide representation in adult tissues may be related to the existence of a circulating blood pool or that MSCs are associated to the vascular system.

 

MSCs have been isolated in the sixties by Friedenstein from the bone marrow of adult animals as plastic-adherent cells developing colonies of cells; these colonies are clones and the initiating cell is called a colony-forming unit- fibroblasts (CFU-f).

 

Transplantion of these colonies into animals resulted in the bone being of the same origin as the transplanted colony. In the laboratory these same colonies support hematopoiesis (blood development) for months . A subset of stromal cells forms the hematopoietic niche where HSCs fixed by surrounding microenvironmental cells maintain their self-renewal potential. This historical background underlines that cells representing an essentially identical entity may be obtained in different culture systems, hence the different denominations: Mesenchymal Stem Cells, Mesenchymal Progenitor Cells, Marrow Stromal cells, Skeletal Stem Cells.