Sources and Clinical Applications of Mesenchymal Stem Cells

Stem cells can be distinguished based on their differentiation potential and source within the human body. Embryonic stem cells are totipotent, because they can form both embryonic and extra-embryonic structures.1 Furthermore, embryonic stem cells can proliferate indefinitely under specific culture conditions and retain the ability to differentiate into cell types of the three embryonic germ layers.1,2 In contrast, adult stem cells are undifferentiated multipotent stem cells obtained from adult individuals and differentiate into the cell types that constitute their respective source tissues; accordingly, cells originating from neuronal tissue can differentiate into neurons, oligodendrocytes or astrocytes. This characteristic plasticity is an attribute of mesenchymal stem cells (MSCs), which are unspecialised cells with the ability to self-renew.3,4

Human MSCs are plastic-adherent cells that differentiate into cells that originate from the ectoderm and endoderm.35 Moreover, they can abandon their unspecialised or undifferentiated states and transform into other mesenchymal lineages. Thus, they can regenerate bone, cartilage and fat and even become endothelial cells, muscle cells or neurons under physiological and experimental conditions.3,4 While evidence suggests that MSCs are present in almost all human tissues, they were first isolated from mononuclear cells derived from bone marrow (BM).3,6

As MSCs are responsible for tissue repair, growth, wound healing and cell substitution resulting from physiological or pathological causes, they have various therapeutic applications such as in the treatment of central nervous system afflictions like spinal cord lesions.4 Moreover, because of their differentiation ability, MSCs have become the de facto model for regenerative medicine research.3,5,6 In the field of regenerative medicine, MSCs have several advantages over other types of stem cells. For example, from an ethical standpoint, the controversy that surrounds the procurement of embryonic stem cells is virtually nonexistent in the case of induced pluripotent stem cells or MSCs, although teratogenicity limits the widespread use of the former cell type.3,4,6

The objective of the current review was to highlight the available information regarding MSC sources and their potential applications in the treatment of a variety of diseases. However, in order to present a comprehensive overview of the possible clinical applications of MSCs, it is first necessary to understand their unique characteristics, including their differentiation potential, activity and therapeutic effects in various human systems and tissues.

Stem cells can be isolated from various sources in the human body, the selection of which should ideally be based on their logistical, practical and in vitro characteristics. Currently, the main sources of MSCs are BM and adipose tissue (AT).6 Although MSCs can hypothetically be obtained from almost any tissue within the human body, there are practical limitations concerning the difficulty and invasiveness of the procurement process and various donor characteristics. To select an adequate cell source, the practitioner must consider the difficulty of procuring the samples and the potential adverse effects of harvesting the cells on the donor. Obtaining BM-MSCs, for example, can result in pain, bleeding or infection, thus making harvesting MSCs from this source more problematic than harvesting cells from peripheral blood or surgical remnants such as AT or birth-derived tissues.9 Table 1 describes current sources of MSCs along with their characteristics, advantages, disadvantages and clinical applications. 7,930

Comparison of mesenchymal stem cell sources and their characteristics7,930

Adipocytes

Astrocytes

Cardiomyocytes

Chondrocytes

Hepatocytes

Mesangial cells

Muscle cells

Neurons

Osteoblasts

Stromal cells

Embryonic tissue

Stem cells from this source have the potential to differentiate into hepatocytes, much like AT-MSCs.

These cells express cytochrome p450.

Multiple clinical trials have confirmed the safety and effectiveness of this type of stem cell.

Generation of pancreatic cells in vitro.

Treatment of orthopaedic conditions characterised by large bone defects, including articular cartilage repair and osteoarthritis, rheumatoid arthritis, rotator cuff injuries and tendon, spinal cord and meniscus lesions.

BM-MSCs may also be used to treat non-unions, osteonecrosis of the femoral head and to promote growth in osteogenesis imperfecta.

Potentially promising treatment for myocardial infarction, as well as GVHD, SLE and MS.

In animal models, BM-MSCs have been studied in the context of autoimmune encephalomyelitis, asthma, allergic rhinitis, pulmonary fibrosis and peripheral nerve regeneration.

Mean doubling time of 40 hours.

Proliferation capacity increases after passage six.

Contact inhibition of proliferation.

Senescence by passage seven.

Adipocytes

Chondrocytes

Osteocytes

Muscle cells

This source results in the isolation of up to 500 times more stem cells than BM (i.e. 5 103 cells from 1 g of AT).

AT is accessible and abundant and secretes several angiogenic and antiapoptotic cytokines.

The immunosuppressive effects of AT-MSCs are stronger than those of BM-MSCs.

Immunosuppressive GVHD therapy.

Potential for cell-based therapy for radiculopathy, MI and neuropathic pain.

Cosmetic/dermatological applications.

Successfully used in the treatment of skeletal muscle injuries, meniscus damage and tendon, rotator cuff and peripheral nerve regeneration.

Mean doubling time of 4 1 days (5 1 days for omental fat).

Cells proliferate faster than BM-MSCs.

Region-dependent (subcutaneous).

Odontoblasts

Osteoblasts

Adipocytes

Chondrocytes

Neurogenic cells

Myogenic cells

As dental surgeries are fairly common, the source materials for these cells are easily accessible.

The frequency of colony-forming cells from dental pulp is high compared to those from BM (2270 colonies versus 2.43.1 colonies/104 cells plated).

These cells have an ectomesenchymal origin (i.e. are derived from neural crest cells).

Dental pulp-derived stem cells can differentiate into mesenchymal linages both in vitro and in vivo.

PCy-MSCs have recently attracted interest because of their neural and bone differentiation potential.

Dental pulp and periodontal ligament stromal cells are the main types of cells.

The benefits of this source includes high availability and the avoidance of invasive procedures and ethical issues.

These stem cells demonstrate higher expansion and engraftment capacity than BM-MSCs.

UCB-MSCs also possess osteogenic differentiation capabilities.

UCB-MSCs produce 2.5-fold more insulin than BM-MSCs.

UCB-MSCs may not have adipogenic potential.

In terms of osteogenesis potential, this source is not as useful as BM, blood or the liver.

Mean doubling time is 30 hours (this remains constant for passages 110).

Multilayered proliferation.

UCB-MSCs do not age over passages (i.e. senescence).

Potential treatment for nerve injuries or neuronal degenerative diseases.

Bladder regeneration and kidney, lung, heart, heart valve, diaphragm, bone, cartilage and blood vessel formation.

High self-renewal capacity (>300 cell divisions).

Doubling time of 36 hours.

These cells maintain a normal karyotype, even at late passages.

The phenotype of these cells is similar to that of BM-MSCs.

These cells produce immunosuppressive factors and express certain human embryonic stem cell markers.

Treatment for skin and ocular diseases, inflammatory bowel disease, lung injuries, cartilage defects, Duchenne muscular dystrophy, stroke and DM.

Peripheral nerve regeneration.

Adipocytes

Fibroblasts

Osteoblasts

Osteoclasts

Chondrocytes

Colony-forming efficiency ranges from 1.213 colonies per million mononuclear cells.

A large volume of blood and, therefore, a greater quantity of MSCs can be collected compared to BMMSCs (up to 1.91 0.21 mL of mobilised peripheral blood yields 197.8 24.9 106 cells/mL versus 21.6 2.7 106 cells/mL of BM).

The amount of MSCs obtained from this source varies greatly (0.0010.01%).

Cells from this source have lower osteogenic and chondrogenic potential and higher adipogenic potential than BM-MSCs.

No clinical trials have been conducted to assess the safety and effectiveness of this type of stem cell.

Adipocytes

Chondrocytes

Osteoblasts

Chondrocytes

Adipocytes

Osteoblasts

Smooth muscle cells

Myocardial cells

Hepatocytes

If isolated from menstrual blood, this source is minimally invasive.

Use of these cells may facilitate understanding of gynaecological diseases such as endometrial carcinoma and endometriosis.

Treatment for Duchenne muscular dystrophy, muscle repair, limb ischaemia and myocardial infarction.

Other applications include type 1 DM, stroke, ulcerative colitis, endometriosis, endometrial carcinoma, pelvic prolapse and cardiac failure.

High proliferation capacity of 6 1011 cells from a single cell.

Doubling time of 1836 hours.

These cells can maintain a relatively stable karyotype over 40 passages.

Chondral cells

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Sources and Clinical Applications of Mesenchymal Stem Cells