Regenerative Medicine – Basics are a must !

INTRODUCTION

• There are a myriad of musculoskeletal disease conditions and injuries that presently have limited therapeutic options and could benefit from developing technologies in regenerative medicine.

• The goal of regenerative medicine is to functionally repair tissues and organs using cell-based techniques, thereby avoiding the need for artificial replacement therapies.

• Within this field, stem cells hold great potential as a method to either stimulate repair through systemic/local delivery or grow new organ systems de novo through tissue engineering technologies.

• Despite rapid progress, significant challenges remain in the translation of these stem cell therapies for clinical applications.

WHAT MAKES A CELL A “STEM CELL”?

• The phrase “stem cell” has become so commonly used and misused that the rigor behind its scientific meaning has, in many cases, been lost.

• For a cell to be a stem cell, by definition, it must have the capacity to differentiate into multiple types of cells and the cell must be able to self-renew. The ability of a stem cell to simultaneously maintain the stem cell pool and generate daughter cells that can terminally differentiate into numerous tissues describes the unique capability of stem cells to undergo asymmetric cell division.

• This contrasts with somatic cells that divide symmetrically to create two identical daughter cells with the same potential. When activated during fetal development or in disease/repair states, stem cells can also undergo symmetrical cell division and rapid proliferation, but they typically remain relatively quiescent

NOT ALL STEM CELLS ARE THE SAME!

Totipotent stem cells

• Even after meeting the scientific requirements necessary to be classified as a “stem cell,” there is a highly variable capacity for differentiation.

• The number and types of progeny cells that an individual stem cell can produce define its “potency.”

• Totipotent stem cells are the most potent stem cell type, and can differentiate to form all of the embryonic and extraembryonic cells (such as the placenta) in an organism.

• Totipotent stem cells are generally obtained at, or before, the morula stage (an early, preimplantation stage of an embryo representing the 2–32 cell stage of development).

Pluripotent stem cells

• As the embryo continues to divide, stem cell potency becomes more restricted. At the blastocyst stage, the cells divide into two “pluripotent” stem cell populations: embryonic and extraembryonic.

• The word pluripotent comes from the Latin “plurimus” (very many) and “potentia” or (powered) and refers to the ability of these cells to differentiate into a diverse set of progeny.

• Embryonic stem cells (ESCs) are found in the inner cell mass of a blastocyst and can generate all of the cells of the embryo.

• The trophoectoderm of the blastocyst contains the extraembryonic (trophoblast) stem cells, which can populate the placenta.

Adult stem cells

• Adult stem cells are part of a “multipotent” cell population that is maintained and accessible in stem cell niches.

• These cells typically only generate progenitor cells along a specific cell lineage, and are therefore significantly more restricted in potential than the pluripotent stem cells.

• Hematopoetic stem cells found in the bone marrow, epidermal stem cells found in the bulge of the hair follicle, and intestinal stem cells found in the intestinal villus crypt are examples of adult stem cells and their associated niches.

Mesenchymal stem cells

• Of the adult stem cells, mesenchymal stem cells (MSCs) are probably the most interesting for orthopedic applications because of their potential to differentiate to both bone and cartilage.

• This population of progenitor cells was first identified by Friedenstein et al. as a population of mononuclear, fibroblast-like tissue culture adherent cells capable of colony formation.

• Subsequently, it has been repeatedly demonstrated that these cells are multipotent and the classic definition now includes a minimal ability to differentiate toward adipose, bone, and cartilage tissues in vitro.

• Differentiation toward other skeletal or mesenchymal cell types including tendon/ligament,muscle, and stromal tissue has been demonstrated, but not rigorously vetted. Similarly, the ability of MSCs to regenerate non-mesenchymal lineages, such as cardiac, neuronal, and skin tissues, has been reported.

• However, more recent research on this phenomenon demonstrates that engraftment and direct differentiation of MSCs into these cell types is minimal, suggesting their effect is likely due to a stimulation of the innate repair responses within these tissues.

• MSCs have been isolated from a number of tissue sources including bone marrow, adipose tissue,periosteum, and the synovial lining.

• Interestingly, pericytes (also called adventitial reticular cells) appear to have the same defining characteristics as MSCs, bringing into question whether the perivasculature is another MSC niche or if these cells represent some precursor population.