Mesenchymal Stem Cells  - Development and Stem Cells

Embryonic and Postnatal Development of Mesenchymal Stem Cells:

Like other stem cells which reside in pre-natal, adult tissues and organs, mesenchymal stem cells (MSCs; also known as multipotent mesenchymal stromal cells) are capable of self-renewal and multipotential differentiation. MSCs are considered adult or somatic stem cells and remain in a non-proliferative, quiescent state during most of their lifetime, until stimulated by the signals triggered by tissue renewal, damage and remodeling processes. When derived from fetal membranes, such as chorionic and amniotic membranes, MSCs are considered an intermediate between human embryonic stem cells (hESCs) and adult stem cells. Several fetal and adult MSC sources have been identified so far, however genuine proof for the ability of the derived cells to function as MSCs have been postulated mainly by their phenotypic characterization in vitro. Recent publications support the hypothesis that MSCs develop from the blood vessel wall and belong to a subset of perivascular cells (i.e., pericytes).  However, some MSCs may originate in other cell niches.

In our attempts to map the embryonic and adult origin of MSCs, several sources (i.e., tissues and organs) shown to contain presumptive MSCs, characterized by known and rather newly identified markers, have been annotated in LifeMap Discovery. In this regard, known markers such as NT5E (CD73), ENG (endoglin; CD105), THY1 (CD90) are shared by both in vitro and in vivo MSCs, however other annotated markers such as STRO-1, D7-FIB, MSCA-1 (W8B2), NGFR (CD271) appear to be rather specific to in vivo MSCs. Moreover, other embryonic or adult MSC sources have been postulated (e.g., neuroectoderm origin), however, their in vivo characterization or contribution to the overall MSC pool is poorly understood. In this regard, comprehensive cell lineage tracking experiments will significantly promote our current knowledge regarding the in vivo origin and function of MSCs.

In vivo MSC sources:

1. Bone-marrow MSCs

Bone marrow was the first MSC source to be discovered.  These cells, often referred to as bone marrow stroma cells, develop during bone formation, from the early osteoprogenitor cells which later invade along the forming blood vessel and enter the bone marrow. At postnatal stages, the bone marrow contains a mixture of cells, including hematopoietic stem cells (HSCs), adipose cells and fibroblasts, with MSCs making up 0.001-0.01% of the total population.

2. Periosteum-derived MSCs

Periosteum is a specialized connective tissue that forms a fibrovascular membrane covering all bone surfaces, with the exception of articular cartilage and sesamoid bones. Periosteum-derived MSCs comprise a significant subpopulation of cells within the periosteum, which develops during prenatal and postnatal stages. The periosteum is a mixed cell population of fibroblasts, osteoblasts, MSCs, and pericytes cells.

3. Pericytes and adventitial reticular cells

Pericytes and adventitial reticular cells (ARCs) are perivascular cells, found in many tissues, which are recruited to blood-vessel walls from the surrounding tissue during organ development and growth. Perivascular cells, including pericytes in the smallest blood vessels (e.g., microvessels) and ARCs  around larger ones, express mesenchymal stem cell markers and bear a multi-differentiation fate potential (differentiate into osteoblasts, chondrocytes, adipocytes, smooth muscle cells and myocytes) similar to that documented for MSCs in vitro. Additionally, cells expressing MSC markers were found to localize to blood vessel walls in human bone marrow and dental pulp. Thus far, a prevailing dogma in the field has led scientists to propose that MSCs are distributed throughout the post-natal organism life as vascular pericytes, however this dogma needs further authentication (see important remarks)

4. Adipose MSCs

The postnatal adipose tissue contains a heterogeneous population of cells which includes adult stem cells (i.e., MSCs), endothelial progenitor cells, leukocytes, endothelial cells, and vascular smooth muscle cells. Adipose MSCs, sometimes referred to as stromal vascular cells, putatively develop from embryonic lateral plate mesenchymal stem cells, along with the common preadipocyte, which give rise to the different mature adipose cells. Adipose MSCs are concentrated in white subcutaneous depots; however they can be found, to a lesser extent, in white visceral depots.

5. Dental pulp MSCs

The dental mesenchyme, which is the origin of all the five tooth stem cell types, is known to derive from the cranial neural crest (CNC) during their embryonic development within the branchial arch 1 (BA1) region (i.e., head mesenchyme).  These five types of stem cells are described in the Discovery database as a general dental pulp stem cell population, which includes the following stem cell types: dental pulp stem cell (DPSCs), stem cells from exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSCs), stem cells from apical papilla (SCAP), and dental follicle progenitor cells (DFPCs).

6. Fetal membranes and tissues as an MSC source:

The umbilical cord and perinatal tissue are rich sources of stem cells. Multipotent stem cells have been found in the chorion, placenta, amnion, amniotic fluid, and in the tissue surrounding the umbilical cord vessels, i.e., Wharton's jelly, and in the umbilical cord itself. Unlike other fetal-derived stem cell origin, the amniotic fluid contains cells that arise from the developing fetus, at ratios and from origins that vary throughout pregnancy. While adult MSCs are multipotent by nature, some fetal stem cells are considered pluripotent and can differentiate into lineages of all three germ layers.

MSC function in normal and pathophysiological conditions:

To date, there is no commonly accepted assay which has been established to measure the physiological activity of MSCs in vivo. While it is generally accepted that MSC are mostly quiescent during postnatal life, MSCs in different niches can presumably differentiate into the specific cells of closely related niches during physiological turnover, injury or disease, as shown for other stem cell types (e.g., muscle satellite cells). The most commonly known MSC function is the ability to form stromal precursor cells, which differentiate into three types of cells: osteoblasts (i.e., bone), chondrocytes (i.e., cartilage), and adipocytes (i.e., adipose). Practically, MSCs can function and progress through distinct stages of differentiation to give rise to different functionally mature tissues types, including smooth and skeletal muscle, tendon and ligaments and even neurons. Furthermore, these potentials are expanded by the notion that MSCs can exert functions other than those classically attributed to stem or progenitor cells, including establishment and support of the hematopoietic microenvironment in vivo, as observed for bone marrow derived MSCs.

Important remarks regarding MSC development and function:

The outbreak of interest in the therapeutic potential of human MSCs has raised several key issues which must be addressed. The variable marker profiles used to identify such cells must be standardized and ideally should reflect the MSC origin.

While pericytes, to some extent, meet MSC characterization criteria (e.g., shared markers and fate potentials), 'non-pericyte' MSCs have been isolated from articular cartilage, which is an avascular tissue, arguing that MSCs are not exclusively located in a perivascular niche. Furthermore, despite growing circumstantial evidence that pericytes might be the in vivo native counterparts of the ex vivo MSCs, there has been no direct evidence (by prospective cell lineage tracking experiments) that pericytes display key features of stem cells including proliferation and differentiation into mature cell phenotypes in vivo following injury. The question therefore remains open as to whether the MSCs make up a unique cell type, distinct from the vascular pericyte, with a specific function to replace mature mesenchymal cells lost during normal physiological processes, injury or disease; or if there are multiple subsets of MSCs or progenitor cells, which might be functionally distinct and include both pericytes and other MSC sources.

Understanding the in vivo MSC niches and their molecular and signaling regulation in health and disease is of great value in design of MSCs-based regenerative medicine approaches. Such insight will uncover the manner by which these cells exit from the quiescent state and become activated and drawn towards sites of inflammation and injury in order to trigger and enhance tissue regeneration.