Stromal Cells

Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucosa (endometrium), prostate, bone marrow, lymph node and the ovary. They are cells that support the function of the parenchymal cells of that organ. The most common stromal cells include fibroblasts and pericytes. The term ''stromal'' comes from Latin , "bed covering", and Ancient Greek , , "bed".

Stromal cells are an important part of the body's immune response and modulate inflammation through multiple pathways. They also aid in differentiation of hematopoietic cells and forming necessary blood elements. The interaction between stromal cells and tumor cells is known to play a major role in cancer growth and progression. In addition, by regulating local cytokine networks (e.g. M-CSF, LIF), bone marrow stromal cells have been described to be involved in human hematopoiesis and inflammatory processes.

Stromal cells (in the dermis layer) adjacent to the epidermis (the top layer of the skin) release growth factors that promote cell division. This keeps the epidermis regenerating from the bottom while the top layer of cells on the epidermis are constantly being "sloughed" off the body. Additionally, stromal cells play a role in inflammation responses, and controlling the amount of cells accumulating at an inflamed region of tissue.

Defining a stromal cell

Defining a stromal cell is of importance because it was a source of difficulty in the past. Without a strong definition studies could not cross over or gain knowledge from each other because a stromal cell was not well defined and went by a plethora of names. A stromal cell is currently more specifically referred to as a mesenchymal stromal cell (MSC). It is non-hematopoietic, multipotent, and self-replicating. These factors make it an effective tool in potential cell therapies and tissue repair. Being a mesenchymal cell indicates an ability to develop into various other cell types and tissues such as connective tissue, blood vessels, and lymphatic tissue. Some stromal cells can be considered stem cells but not all therefore it can not be broadly termed a stem cell. All MSCs have the ability adhere to plastic and replicate by themselves. The minimal criteria to define MSCs further include a specific set of cell surface markers. The cells must express CD73, CD90 and CD105 and they must be negative for CD14 or CD11b, CD34, CD45, CD79 alpha or CD19 and HLA-DR. Low levels of human leukocyte antigen (HLA-DR) make MSCs hypoimmunogenic. MSCs have trilineage differentiation capacity where they are able to adapt into osteoblast, chondrocytes, and adipocytes. They can also display anti-inflammatory as well as proinflammatory responses allowing for the potential to help with a broad range of immune disorders and inflammatory diseases.

Sources of stromal cells

It is well known that stromal cells arise and are stored in the bone marrow until maturation and differentiation. They are located in the stroma and aid hematopoietic cells in forming the elements of the blood. While a majority is found in the bone marrow scientists now know that stromal cells can be found in a variety of different tissues as well. These can include adipose tissue, endometrium, synovial fluid, dental tissue, amniotic membrane and fluid, as well as the placenta. High quality stromal cells are located in the placenta, due to their young age. MSCs lose function with age, and aged MSCs are less efficacious in therapy.

Role in cancer

During normal wound healing processes, the local stromal cells change into reactive stroma after altering their phenotype. However, under certain conditions, tumor cells can convert these reactive stromal cells further and transition them into tumor-associated stromal cells (TASCs). In comparison to non-reactive stromal cells, TASCs secrete increased levels of proteins and matrix metalloproteinases (MMPs). These proteins include fibroblast activating protein and alpha-smooth muscle actin. Furthermore, TASCs secrete many pro-tumorigenic factors such as vascular endothelial growth factor (VEGF), stromal-derived factor-1 alpha, IL-6, IL-8, tenascin-C, and others. These factors are known to recruit additional tumor and pro-tumorigenic cells. The cross-talk between the host stroma and tumor cells is essential for tumor growth and progression. Tumor stromal production exhibits similar qualities as normal wound repair such as new blood vessel formation, immune cell and fibroblast infiltration, and considerable remodeling of the extracellular matrix.

Additionally, the recruitment of local normal host stromal cells, such as bone marrow mesenchymal stromal cells, endothelial cells, and adipocytes, help create a conspicuously heterogeneous composition. Furthermore, these cells secrete an abundance of factors that help regulate tumor development. Potential targets for tumor-associated stromal cell recruitment have been identified in the following host tissue: bone marrow, connective tissue, adipose tissue, and blood vessels. Moreover, evidence suggests that tumor-associated stroma are a prerequisite for metastasis and tumor cell invasion. These are known to arise from at least six different origins: immune cells, macrophages, adipocytes, fibroblasts, pericytes, and bone marrow mesenchymal stromal cells.
Furthermore, the tumor stroma is primarily composed of the basement membrane, fibroblasts, extracellular matrix, immune cells, and blood vessels. Typically, most host cells in the stroma are characterized by tumor-suppressive abilities. However, during malignancy, the stroma will undergo alterations to consequently incite growth, invasion, and metastasis. These changes include the formation of carcinoma-associated fibroblasts (CAFs) which comprises a major portion of the reactive tissue stroma and plays a critical role in regulating tumor progression.

Certain types of skin cancers (basal cell carcinomas) cannot spread throughout the body because the cancer cells require nearby stromal cells to continue their division. The loss of these stromal growth factors when the cancer moves throughout the body prevents the cancer from invading other organs.

Stroma is made up of the non-malignant cells, but can provide an extracellular matrix on which tumor cells can grow. Stromal cells may also limit T-cell proliferation via nitric oxide production, hindering immune capability.

Immunomodulatory effects

Anti-inflammatory

An important property of MSCs is their ability to suppress an excessive immune response. T-cells, B-cells, dendritic cells, macrophages, and natural killer cells can be overstimulated during an ongoing immune response, but stromal cells help to keep the balance and make sure the body can properly heal without an excessive amount of inflammation. Thereby, they also help prevent autoimmunity.

MSCs can affect cells of the adaptive immune system as well as cells of the innate immune system. For example, they can inhibit the proliferation and activity of T-cells When there is a high level of MSCs during an immune response the generation of more B-cells is stunted. The B-cells that can still be produced are impacted by diminished antibody count production and chemotactic behavior.
Dendritic cells in the presence of MSC's are immature and undifferentiated which causes impaired function to call upon T-cells and bridge the gap between the innate