Mesenchymal stem cell

While the terms mesenchymal stem cell (MSC) and marrow stromal cell have been used interchangeably for many years, neither term is sufficiently descriptive:

• Mesenchyme is embryonic connective tissue that is derived from the mesoderm and that differentiates into hematopoietic and connective tissue, whereas MSCs do not differentiate into hematopoietic cells.[5]
• Stromal cells are connective tissue cells that form the supportive structure in which the functional cells of the tissue reside. While this is an accurate description for one function of MSCs, the term fails to convey the relatively recently discovered roles of MSCs in the repair of tissue.[6]
• The term encompasses multipotent cells derived from other non-marrow tissues, such as placenta,[7] umbilical cord blood, adipose tissue, adult muscle, corneal stroma,[8] or the dental pulp of deciduous (baby) teeth.[9] The cells do not have the capacity to reconstitute an entire organ.

Human bone marrow derived Mesenchymal stem cell showing fibroblast-like morphology seen under phase contrast microscope (carl zeiss axiovert 40 CFL) at 63 x magnification

An example of human mesenchymal stem cells imaged with a live cell imaging microscope

Mesenchymal stem cells (MSCs), a term first coined by Arnold I. Caplan in 1991,[10] are characterized morphologically by a small cell body with a few cell processes that are long and thin. The cell body contains a large, round nucleus with a prominent nucleolus, which is surrounded by finely dispersed chromatin particles, giving the nucleus a clear appearance. The remainder of the cell body contains a small amount of Golgi apparatus, rough endoplasmic reticulum, mitochondria, and polyribosomes. The cells, which are long and thin, are widely dispersed, and the adjacent extracellular matrix is populated by a few reticular fibrils, but is devoid of the other types of collagen fibrils.[11][12] These distinctive morphological features of mesenchymal stem cells can be visualized label-free using live cell imaging.

The International Society for Cellular Therapy (ISCT) has proposed a set of standards to define MSCs. A cell can be classified as an MSC if it shows plastic adherent properties under normal culture conditions and has a fibroblast-like morphology. In fact, some argue that MSCs and fibroblasts are functionally identical.[13] Furthermore, MSCs can undergo osteogenic, adipogenic and chondrogenic differentiation ex vivo. The cultured MSCs also express on their surface CD73, CD90 and CD105, while lacking the expression of CD11b, CD14, CD19, CD34, CD45, CD79a and HLA-DR surface markers.[14]

Bone marrow was the original source of MSCs,[15] and is still the most frequently utilized source. These bone marrow stem cells do not contribute to the formation of blood cells, and so do not express the hematopoietic stem cell marker CD34. They are sometimes referred to as bone marrow stromal stem cells.[16]

The youngest and most primitive MSCs may be obtained from umbilical cord tissue, namely Wharton's jelly and the umbilical cord blood. However, MSCs are found in much higher concentration in the Wharton's jelly compared to cord blood, which is a rich source of hematopoietic stem cells. The umbilical cord is available after a birth. It is normally discarded, and poses no risk for collection. These MSCs may prove to be a useful source of MSCs for clinical applications, due to their primitive properties and fast growth rate.[17]

These cells have several advantages over bone-marrow-derived MSCs. Adipose-tissue-derived MSCs (AdMSCs), in addition to being easier and safer to isolate than bone-marrow-derived MSCs, can be obtained in larger quantities.[15][18]

Apisode-tissue-derived MSCs (AdMSCs), in addition to being easier and safer to isolate than bone-marrow-derived MSCs, can be obtained in larger quantities.

The developing tooth bud of the mandibular third molar is a rich source of MSCs. While they are described as multipotent, it is possible that they are pluripotent. They eventually form enamel, dentin, blood vessels, dental pulp, and nervous tissues. These stem cells are capable of differentiating into chondrocytes, cardiomyocytes, melanocytes, and hepatocyte‐like cells in vitro.[9]

Stem cells are present in amniotic fluid. As many as 1 in 100 cells collected during amniocentesis are pluripotent mesenchymal stem cells.[19]

MSCs have a great capacity for self-renewal while maintaining their multipotency. Recent work suggests that β-catenin, via regulation of EZH2, is a central molecule in maintaining the "stemness" of MSC's.[20] The standard test to confirm multipotency is differentiation of the cells into osteoblasts, adipocytes and chondrocytes as well as myocytes.

MSCs have been seen to even differentiate into neuron-like cells,[21] but doubt remains about whether the MSC-derived neurons are functional.[22] The degree to which the culture will differentiate varies among individuals and how differentiation is induced, e.g., chemical vs. mechanical;[23] and it is not clear whether this variation is due to a different amount of "true" progenitor cells in the culture or variable differentiation capacities of individuals' progenitors. The capacity of cells to proliferate and differentiate is known to decrease with the age of the donor, as well as the time in culture.[24] Likewise, whether this is due to a decrease in the number of MSCs or a change to the existing MSCs is not known.

MSCs have an effect on innate and specific immune cells, and research has shown an ability to suppress tumor growth.[25] MSCs produce many immunomodulatory molecules including prostaglandin E2 (PGE2),[26] nitric oxide,[27] indoleamine 2,3-dioxygenase (IDO), interleukin 6 (IL-6), and other surface markers such as FasL,[28] PD-L1 and PD-L2.[29]

MSCs have an effect on macrophages, neutrophils, NK cells, mast cells and dendritic cells in innate immunity. MSCs are able to migrate to the site of injury, where they polarize through PGE2 macrophages in M2 phenotype which is characterized by an anti-inflammatory effect.[30] Further, PGE2 inhibits the ability of mast cells to degranulate and produce TNF-α.[31][32] Proliferation and cytotoxic activity of NK cells is inhibited by PGE2 and IDO. MSCs also reduce the expression of NK cell receptors - NKG2D, NKp44 and NKp30.[33] MSCs inhibit respiratory flare and apoptosis of neutrophils by production of cytokines IL-6 and IL-8.[34] Differentiation and expression of dendritic cell surface markers is inhibited by IL-6 and PGE2 of MSCs.[35] The immunosuppressive effects of MSC also depend on IL-10, but it is not certain whether they produce it alone, or only stimulate other cells to produce it.[36]

MSC expresses the adhesion molecules VCAM-1 and ICAM-1, which allow T-lymphocytes to adhere to their surface. Then MSC can affect them by molecules which have a short half-life and their effect is in the immediate vicinity of the cell.[27] These include nitric oxide,[37] PGE2, HGF,[38] and activation of receptor PD-1.[39] MSCs reduce T cell proliferation between G0 and G1 cell cycle phases[40] and decrease the expression of IFNγ of Th1 cells while increasing the expression of IL-4 of Th2 cells.[41] MSCs also inhibit the proliferation of B-lymphocytes between G0 and G1 cell cycle phases.[39][42]

MSCs produce several antimicrobial peptides (AMPs) including human cathelicidin LL-37,[43] β-defensins,[44] lipocalin 2[45] and hepcidin.[46] These peptides, together with the enzyme indoleamine 2,3-dioxygenase (IDO), are responsible for the broad-spectrum antibacterial activity of MSCs.[47]

Clinical studies investigating the efficacy of mesenchymal stem cells in treating diseases are in clinical development around the world, particularly treating autoimmune diseases, graft versus host disease, Crohn's disease, multiple sclerosis, systemic lupus erythematosus and systemic sclerosis.[49][50]

Many of the early clinical successes using intravenous transplantation came in systemic diseases such as graft versus host disease and sepsis. Direct injection or placement of cells into a site in need of repair may be the preferred method of treatment, as vascular delivery suffers from a "pulmonary first pass effect" where intravenous injected cells are sequestered in the lungs.[51]

Further studies into the mechanisms of MSC action may provide avenues for increasing their capacity for tissue repair.[52][53]