Mesenchymal stem cell

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Mesenchymal stem cell
MSC high magnification.jpg
Transmission electron micrograph of a mesenchymal stem cell displaying typical ultrastructural characteristics
Details
Identifiers
Latin cellula mesenchymatica praecursoria
MeSH D059630
TH H2.00.01.0.00008
Anatomical terms of microanatomy

Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells or medicinal signaling cells, are multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage cells), myocytes (muscle cells) and adipocytes (fat cells which give rise to marrow adipose tissue). [1] [2] [3] [4]

Contents

Structure

Definition

Mesenchymal stem cells (MSCs), a term first used (in 1991) by Arnold Caplan at Case Western Reserve University, [5] are characterized morphologically by a small cell body with long, thin cell processes. While the terms mesenchymal stem cell (MSC) and marrow stromal cell have been used interchangeably for many years, neither term is sufficiently descriptive:

Morphology

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 Human bone marrow derived MSCs.jpg
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 Human mesenchymal stem cells.gif
An example of human mesenchymal stem cells imaged with a live cell imaging microscope

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. [12] [13] These distinctive morphological features of mesenchymal stem cells can be visualized label-free using live cell imaging.

Classification

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. [14] The study in Science, "Multilineage Potential of Adult Mesenchymal Stem Cells," describes how MSCs can undergo osteogenic, adipogenic and chondrogenic differentiation ex vivo. As of November 2023, this paper has been cited over 29,000 times. 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. [15]

Location in the body

MSCs are found throughout the human body.

Bone marrow

Bone marrow was the original source of MSCs, [16] 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. [17]

Cord cells

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. [18]

Adipose tissue

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. [16] [19]

Molar cells

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. [10]

Amniotic fluid

Stem cells are present in amniotic fluid. As many as 1 in 100 cells collected during amniocentesis are pluripotent mesenchymal stem cells. [20]

Function

Differentiation capacity

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 MSCs. [21] 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, [22] but doubt remains about whether the MSC-derived neurons are functional. [23] The degree to which the culture will differentiate varies among individuals and how differentiation is induced, e.g., chemical vs. mechanical; [24] 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. [25] Likewise, whether this is due to a decrease in the number of MSCs or a change to the existing MSCs is not known.[ citation needed ]

Immunomodulatory effects

MSCs have an effect on innate and specific immune cells, and research has shown an ability to suppress tumor growth. [26] MSCs produce many immunomodulatory molecules including prostaglandin E2 (PGE2), [27] nitric oxide, [28] indoleamine 2,3-dioxygenase (IDO), interleukin 6 (IL-6), and other surface markers such as FasL, [29] PD-L1 and PD-L2. [30]

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. [31] Further, PGE2 inhibits the ability of mast cells to degranulate and produce TNF-α. [32] [33] 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. [34] MSCs inhibit respiratory flare and apoptosis of neutrophils by production of cytokines IL-6 and IL-8. [35] Differentiation and expression of dendritic cell surface markers is inhibited by IL-6 and PGE2 of MSCs. [36] 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. [37]

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. [28] These include nitric oxide, [38] PGE2, HGF, [39] and activation of receptor PD-1. [40] MSCs reduce T cell proliferation between G0 and G1 cell cycle phases [41] and decrease the expression of IFNγ of Th1 cells while increasing the expression of IL-4 of Th2 cells. [42] MSCs also inhibit the proliferation of B-lymphocytes between G0 and G1 cell cycle phases. [40] [43]

Antimicrobial properties

MSCs produce several antimicrobial peptides (AMPs), including human cathelicidin LL-37, [44] β-defensins, [45] lipocalin 2 [46] and hepcidin. [47] These peptides, together with the enzyme indoleamine 2,3-dioxygenase (IDO), are responsible for the broad-spectrum antibacterial activity of MSCs. [48]

Clinical significance

Typical gross appearance of a tubular cartilaginous construct engineered from amniotic mesenchymal stem cells Typical gross appearance of a tubular cartilaginous construct engineered from amniotic mesenchymal stem cells..jpg
Typical gross appearance of a tubular cartilaginous construct engineered from amniotic mesenchymal stem cells

Mesenchymal stem cells can be activated and mobilized in reaction to injury and infection. As of May 2024, a search for "mesenchymal stem cells" or "mesenchymal stromal cells" at ClinicalTrials.gov returns more than 1,760 studies featuring MSCs [49] for more than 920 conditions.

Autoimmune disease

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. [50] [51]

Other diseases

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. [52]

Further studies into the mechanisms of MSC action may provide avenues for increasing their capacity for tissue repair. [53] [54]

Research

The majority of modern culture techniques still take a colony-forming unit-fibroblasts (CFU-F) approach, where raw unpurified bone marrow or ficoll-purified bone marrow mononuclear cells are plated directly into cell culture plates or flasks. Mesenchymal stem cells, but not red blood cells or hematopoietic progenitors, are adherent to tissue culture plastic within 24 to 48 hours. However, at least one publication has identified a population of non-adherent MSCs that are not obtained by the direct-plating technique. [55]

Other flow cytometry-based methods allow the sorting of bone marrow cells for specific surface markers, such as STRO-1. [56] STRO-1+ cells are generally more homogenous and have higher rates of adherence and higher rates of proliferation, but the exact differences between STRO-1+ cells and MSCs are not clear. [57]

Methods of immunodepletion using such techniques as MACS have also been used in the negative selection of MSCs. [58]

The supplementation of basal media with fetal bovine serum or human platelet lysate is common in MSC culture. Prior to the use of platelet lysates for MSC culture, the pathogen inactivation process is recommended to prevent pathogen transmission. [59]

New research titled Transplantation of human ESC-derived mesenchymal stem cell spheroids ameliorates spontaneous osteoarthritis in rhesus macaques [60] Various chemicals and methods, including low-level laser irradiation, have been used to increase stem cell proliferation. [61]

History

Scientists Ernest A. McCulloch and James E. Till first revealed the clonal nature of marrow cells in the 1960s. [62] [63] In 1970, Arnold Caplan identified certain conditions by which mesodermal cells differentiate into cartilage or myogenic (muscle) tissue and bone. [64]

An ex vivo assay for examining the clonogenic potential of multipotent marrow cells was later reported in the 1970s by Friedenstein and colleagues. [65] [66] In this assay system, stromal cells were referred to as colony-forming unit-fibroblasts (CFU-f).

Subsequent experimentation revealed the plasticity of marrow cells and how their fate is determined by environmental cues. Culturing marrow stromal cells in the presence of osteogenic stimuli such as ascorbic acid, inorganic phosphate and dexamethasone could promote their differentiation into osteoblasts. In contrast, the addition of transforming growth factor-beta (TGF-b) could induce chondrogenic markers.[ citation needed ]

The first clinical trials of MSCs were completed by Osiris Therapeutics in 1995 when a group of 15 patients were injected with cultured MSCs to test the safety of the treatment. [67] The first regulatory approvals for MSCs were granted conditional approval in 2012 in Canada and New Zealand for treating Graft vs. Host Disease (GvHD) and, subsequently, in Japan to treat Crohn’s Disease-related fistula. [68]

Since then, more than 1,500 clinical trials have been conducted to treat numerous conditions. [69]

Controversies

The term "mesenchymal stem cells" and what constitutes the most scientifically correct meaning for the MSC initialism, has been debated for years. Most mesenchymal cell or "MSC" preps only contain a minority fraction of true multipotent stem cells, with most cells being stromal in nature. Caplan proposed rephrasing MSCs to emphasize their role as "medicinal signaling cells." [70] Within the stem cell field, the shorthand "MSC" has most commonly now come to refer to "mesenchymal stromal/stem cells" because of the heterogeneous nature of the cellular preparations.

There is also growing concern about the marketing and application of unapproved MSCs and mesenchymal stem cells that lack rigorous data to back up these clinical uses into patients by for-profit clinics. [71] [72]

See also

Related Research Articles

<span class="mw-page-title-main">Stem cell</span> Undifferentiated biological cells that can differentiate into specialized cells

In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell in a cell lineage. They are found in both embryonic and adult organisms, but they have slightly different properties in each. They are usually distinguished from progenitor cells, which cannot divide indefinitely, and precursor or blast cells, which are usually committed to differentiating into one cell type.

<span class="mw-page-title-main">Bone marrow</span> Semi-solid tissue in the spongy portions of bones

Bone marrow is a semi-solid tissue found within the spongy portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production. It is composed of hematopoietic cells, marrow adipose tissue, and supportive stromal cells. In adult humans, bone marrow is primarily located in the ribs, vertebrae, sternum, and bones of the pelvis. Bone marrow comprises approximately 5% of total body mass in healthy adult humans, such that a man weighing 73 kg (161 lbs) will have around 3.7 kg (8 lbs) of bone marrow.

<span class="mw-page-title-main">Hematopoietic stem cell</span> Stem cells that give rise to other blood cells

Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the (midgestational) aorta-gonad-mesonephros region, through a process known as endothelial-to-hematopoietic transition. In adults, haematopoiesis occurs in the red bone marrow, in the core of most bones. The red bone marrow is derived from the layer of the embryo called the mesoderm.

<span class="mw-page-title-main">CD34</span> Protein found in humans

CD34 is a transmembrane phosphoglycoprotein protein encoded by the CD34 gene in humans, mice, rats and other species.

<span class="mw-page-title-main">Cell therapy</span> Therapy in which cellular material is injected into a patient

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Cord blood is blood that remains in the placenta and in the attached umbilical cord after childbirth. Cord blood is collected because it contains stem cells, which can be used to treat hematopoietic and genetic disorders such as cancer.

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 stromat-, "bed covering", and Ancient Greek στρῶμα, strôma, "bed".

<span class="mw-page-title-main">Adult stem cell</span> Multipotent stem cell in the adult body

Adult stem cells are undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells, they can be found in juvenile, adult animals, and humans, unlike embryonic stem cells.

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References

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