Mesenchymal Stem Cells


A. Introduction
Mesenchymal stem cells are characterized as anti-flammatory, antifibrotic, antimicrobial and regenerative. Through cell-cell interactions and through the production of bioactive secreted factors including small proteins, chemokines, cytokines, and other cellular regulators, mesenchymal stem cells can induce new blood vessel development (angiogenesis) and induce cellular recruitment.
Sutton MT, Bonfield TL. Stem Cells: Innovations in clinical applications. Stem Cells Int 2014; 2014:516278. on-line reference


1. Mesenchymal Stem Cells and Immune Suppression

Mesenchymal stem cells are anti-inflammatory. This can be a good thing for those with inflammatory conditions. However, treatments with too many mesenchymal stem cells could lower the immune response and set the stage for the progression of infections or the risk of cancer.
Arango-Rodriguez ML, Ezquer F, Ezquer M, Conget P. Could cancer and infection be adverse effects of mesenchymal stromal cell therapy? World J Stem Cells 2015;7(2):408-17. on-line reference


2. Mesenchymal Stem Cell Differentiation

Mesenchymal stem cells have the capacity to differentiate into osteocytes (bone cells), adipocytes (fat cells), condrocytes (for cartilage), neurons and liver cells. While mesenchymal stem cells have niches (homes) in the bone marrow, they also found in amniotic fluid, endometrium, dental tissues, umbilical cord and Wharton's jelly.
Ullah I, Baregundi Subbarao R, Rho GJ. Human Mesenchymal Stem Cells - Current trends and future prospective. Biosci Rep 2015; Mar 23 [Epub ahead of print] on-line reference


3. Mesenchymal Stem Cells and Growth Factors

Some of the growth factors that mesenchymal stem cells induce include bone morphogenetic proteins (BMPs), epidermal growth factors (EGF), transforming growth factor (TGF), and fibroblast growth factor (FGF). Bhaskar B, Mekala NK, Baadhe RR, Rao PS. Role of signaling pathways in mesenchymal stem cell differentiation. Curr Stem Cell Res Ther 2014;9(6):508-12. on-line reference


4. Mesenchymal Stem Cells from Umbilical Cord Blood derived Stem Cells

Human umbilical cord is a promising source of mesenchymal stem cells. Unlike bone marrow stem cells, mesenchymal stem cells from umbilical cord blood have a painless collection procedure and faster self-renewal properties.
Ding DC, Chang YH, Shyu WC, Lin SZ. Human umbilical cord mesenchymal stem cells: a new era for stem cell therapy. Cell Transplant 2015;24(3):339-47. on-line reference


5. Mesenchymal stem cells and Mobilization

Parathyroid hormone treatment is able to induce mobilization of bone marrow progenitor cells into the bloodstream and expand the bone marrow stem cell niche.
Huber BC, Grabmaier U, Brunner S. Impact of parathyroid hormone on bone marrow-derived stem cell mobilization and migration. World J Stem Cells 2014;6(5):637-43. on-line reference


6. Mesenchymal stem cells and Extracellular Vesicles or Exosomes

Extracellular vesicles are released from mesenchymal stem cells that contain miRNA, mRNA and proteins. These products have a significant safety profile and can be safely stored without losing function. The authors suggest that extracellular vesicles (EVs) could have a promising future as an alternative, cell-free therapy.
Rani S, Ryan AE, Griffin MD, Ritter T. Mesenchymal Stem Cell-derived Extracellular Vesicles: Toward Cell-free Therapeutic Applications. Mol Ther 2015 [Epub ahead of print] on-line reference


7. Mesenchymal stem cells and Oxidative Stress

Free radicals are produced by normal energy metabolism. These free radicals are absorbed by or taken out of the system by antioxidants such as glutathione, catalase and superoxide dismutase. However, when the antioxidant defense system is overwhelmed and fails to reduce the level of free radicals to their normal levels, the condition is called "oxidative stress." Oxidative stress is often characterized by the free radicals oxidizing (rusting/damaging) lipids, proteins, RNA and DNA. This process can lead to mutations, the risk of cancer and aging. Mesenchymal stem cells are useful in the treatment of conditions associated with oxidative stress. These stem cells appear to effectively manage oxidative stress and be more resistant to oxidative insult than normal somatic cells. The authors discuss the role of oxidative stress in human mesenchymal stem cell aging.
Benameur L, Charif N, Li Y, Stoltz JF, de Isla N. Toward an understanding of mechanism of aging-induced oxidative stress in human mesenchymal stem cells. Biomed Mater Eng 2015;25(1 Suppl):41-6. on-line reference


8. The Bone Marrow Niche

The bone marrow niche consists of mesenchymal stem cells and hematopoietic stem cells. These stem cells persist lifelong in the organism, where they are responsible for tissue homeostasis and repair. Their maintenance and function are facilitated in local environments called the "stem cell niche," in this case, the bone marrow niche.
Krinner A, Roeder I. Quantification and modeling of stem cell-niche interaction. Adv Exp Med Biol 2014;844:11-36. on-line reference


a. Chemokines and the Bone Marrow Niche

Chemokines are secreted from different cellular components of the bone marrow and play an important role in the formation of the bone marrow niche system. The chemokines also influence the fate of hematopoietic stem cell pools located in specialized sites within the bone marrow. MicroRNAs (miRNAs) have an inhibiting function and have the ability to reduce the production and expression of chemokines and chemokine receptors.
Ahmadzadeh A, Kast RE, Ketabchi N,Shahrabi S, Shahjahani M, Jaseb K, Saki N. Regulatory effect of chemokines in bone marrow niche. Cell Tissue Res 2015 [Epub ahead of print] on-line reference


b. Hypoxia and the Niche

An important part of the bone marrow niche is reduced oxygen (hypoxia). If the oxygen partial pressure is 1%, it promotes cell cycle arrest and cell dormancy.
Drolle H, Wagner M, Vasold J, Kütt A, Deniffel C, Sotlar K, Sironi S, Herold T, Rieger C, Fiegl M. Hypoxia regulates proliferation of acute myeloid leukemia and sensitivity against chemotherapy. Leuk Res 2015 [Epub ahead of print] on-line reference


9. Bone vs Fat

Mesenchymal stem cells differentiate into both bone and adipose tissue (fat). If fat is produced, then bone tissue is not produced which can lead to reductions in bone mineral density and bone mass.
Tian L, Yu X. Lipid metabolism disorders and bone dysfunction - interrelated and mutually regulated (Review). Mol Med Rep 2015;12(1):783-94. on-line reference


10. Mesenchymal Stem Cells and Aging

Mesenchymal stem cell aging is characterized by chronic inflammation, bone loss, reduced cell adaptation, reduced tissue repair and impaired differentiation of osteoblasts that form the bone structure and increased osteoclasts that reduce the bone structure.
Abdelmagid SM, Barbe MF, Safadi FF. Role of inflammation in the aging bones. Life Sci 2015; 123C:25-34. on-line reference


B. Treatments

1. Amyotrophic Lateral Sclerosis (ALS)

There are a number of pathologies involved in ALS. One treatment may be the use of mesenchymal stem cells. These cells can differentiate into neuron-like cells and provide a neuroprotective environment for neurological disorders that include ALS.
Allers C, Jones JA, Lasala GP, Minguell JJ. Mesenchymal stem cell therapy for the treatment of amyotrophic lateral sclerosis: signals for hope? on-line reference


b. ALS and Bone Marrow Mononuclear Cells
Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disorder with a fatal prognosis. The authors present the results of a retrospective controlled cohort study of a total of 57 patients. 37 patients underwent autologous bone marrow mononuclear cell (blood cells having a round nucleus) transplantation in addition to standard rehabilitation and Riluzole. The control group consisted of 20 patients who did not receive cell transplantation. The mean survival duration of the intervention group was 87.76 months which was higher than the control group's 57.38 months. Survival duration was significantly higher in those who were below 50 years of age at the onset of the disease.
Sharma AK, Sane HM, Paranjape AA, Gokuchandran N, Nagrajan A, D'sa M, Badhe PB. The Effect of autologous bone marrow mononuclear cell transplantation on the survival duration in Amyotrophic Lateral Sclerosis - a retrospective controlled study. Am J Stem Cells 2015;4(1):50-65. on-line reference


2. Arthritis
Mesenchymal stem cells are immunosuppressive and show benefits in inflammatory arthritis.
Swart JF, Wulffraat NM. Mesenchymal stromal cells for treatment of arthritis. Best Pract Res Clin Rheumatol 2014;28(4):589-603. on-line reference


3. The Bone, Aging and Oxidative Stress
Aging of the bone is associated with osteoporosis and related fractures. Oxidation of the surrounding proteins and amino acids, particularly the aromatic amino acids, has been shown to affect the function of bone marrow mesenchymal stem cells. The authors found that oxidized kynurenine inhibited the proliferation of mesenchymal stem cells and their release of osteogenic markers and alkaline phosphatase. The results support the concept that age-related bone loss may be due to oxidized surrounding amino acids.
El Refaey M, Watkins CP, Kennedy EJ, Chang A, Zhong Q, Ding KH, Shi XM, Xu J, Bollag WB, Hill WD, Johnson M, Hunter M, Hamrick MW, Isales CM. Oxidation of the aromatic amino acids tryptophan and tyrosine disrupts their anabolic effects on bone marrow mesenchymal stem cells. Mol Cell Endocrinol 2015 [Epub ahead of print] on-line reference


b. Regeneration of the Jaw Bone

There is a growing need to regenerate an atrophied jaw bone to allow greater strength for dental implant replacement. Bone tissue engineering uses different scaffold, growth factors and stem cells to induce bone augmentation. The authors review recent studies that use mesenchymal stem cells and endothelial progenitor cells to induce bone augmentation.
Zigdon-Giladi H, Khoury N, Evron A. Adult stem cells in the use of jaw bone regeneration: current and prospective research. Quintessence Int 2015;46(2):125-31 on-line reference


c. Mesenchymal Stem Cells and Skeletal Muscle Regeneration

The skeletal muscle is able to repair damage by its satellite cells. The reduction of these satellite cells lead to fiber substitutions with fat tissue and fibrous tissue and the loss of muscle function. Muscle mesenchymal cells that usually contribute to regeneration differentiate instead to fat cells (adipose tissue) in patients with persistent damage and inflammation of the skeletal muscle.
Sciorati C, Clementi E, Manfredi AA, Rovere-Querini P. Fat deposition and accumulation in the damaged and inflammed skeletal muscle: cellular and molecular players. Cell Mol Life Sci 2015 Feb 18. [Epub ahead of print] on-line reference


d. Mesenchymal Stem Cells and Skeletal Muscle

Much of the research on skeletal muscle has been focused on satellite cells. However, mesenchymal stem cells have more recently come into greater prominence. Animal studies with muscular dystrophies show that stem cells have much to offer in human clinical trials.
Maclean S, Khan WS, Malik AA, Anand S, Snow M. The potential of stem cells in the treatment of skeletal muscle injury and disease. Stem Cells Int 2012;2012:282348. on-line reference


e. Bone Regeneration and Vibration Therapy

Studies suggest that high-frequency, low-magnitude vibration therapy improved bone strength by increasing bone formation and decreasing bone resorption. Mesenchymal stem cell allocation is promoted by vibration signals. Frail patients need low-intensity vibration of 1g or less whereas training exercises for athletes can use higher intensity vibration.
Thompson WR, Yen SS, Rubin J. Vibration therapy: clinical applications in bone. Curr Opin Endocrinol Diabetes Obes 2014;21(6):447-53. on-line reference


4. Cancer and Metastasis

Metastasis causes over 90% of deaths in cancer patients. Hypoxia (low oxygen tension) is usually found in solid tumors and is associated with a poor prognosis. Hypoxia increases the growth of blood vessels for nutrients (angiogenesis), cancer cell survival and metastasis. The authors describe how hypoxia plays a role in metastasis and discuss methods of blocking the process.
Chang J, Erler J. Hypoxia-mediated metastasis. Adv Exp Med Biol 2014;772:55-81. on-line reference


b. Cancer and Inflammation

A number of investigations have bridged the gap between chronic inflammation and cancer, including tumor-associated macrophages and regulatory T cells that cause immunosuppressive conditions and tumor evasion in immune surveillance.
Raposo TP, Bierão BC, Pang LY, Queiroga FL, Argyle DJ. Inflammation and cancer: Till death tears them apart. Vet J 2015 Apr 17 [Epub ahead of print] on-line reference


c. The Cancer Stem Cell
The cancer stem cell theory has provided a new angle in cancer research. The multiple drug resistance of cancer is likely due to the resistance of cancer stem cells. Some of these mechanisms include the cancer stem cell microenvironment and epithelial to mesenchymal transition.
DI C, Zhao Y. Multiple drug resistance due to resistance to stem cells and stem cell treatment progressin cancer (Review). Exp Ther Med 2015;9(2):289-293. on-line reference


d. Cancer stem cells and Flavonoids

Despite recent advances in cancer research, metastasis and recurrence remain the major challenges in cancer management. Flavonoids have inhibitory actions on cancer stem cells and their self-renewal. A variety of plants including flavonol quercetin, have the ability to suppress the stemness markers, epithelial-to-mesenchymal transition and migratory characteristics as well as sensitize the cancer cells to chemotherapeutic drugs. Flavonoids can serve as attractive candidates for novel anticancer agents.
Sak K, Everaus H. Role of flavonoids in future anticancer therapy by eliminating the cancer stem cells. Curr Stem Cell Res Ther 2015;10(3):271-82. on-line reference


5. Cardiovascular Disease and Stem Cells

Chronic Heart Failure
In non-ischemic heart failure, hematopoietic stem cells improved myocardial performance, functional capacity and neurohumoral activation. In ischemic heart failure, cardiosphere-derived cells reduced myocardial scars with an increase in viable tissue and systolic wall thickening. Both autologous and allogeneic mesenchymal stem cells were effective in improving heart function in patients with ischemic heart failure. The authors suggest a more personalized approach by establishing optimal stem cell types, dose and delivery methods for individual patients and their disease state.
Poglajen G, Vrtovec B. Stem cell therapy for chronic heart failure. Curr Opin Cardiol 2015;30(3):301-10. on-line reference


b. Cardiovascular repair
Pluripotent stem cells and mesenchymal stem cells have been effective for myocardial regeneration, angiogenesis and cardiac functional restoration. The authors discuss the advantages and disadvantages of stem cells currently used for cardiovascular repair.
Sun Q, Zhang Z, Sun Z. The potential and challenges of using stem cells for cardiovascular repair and regeneration. Genes Dis 2014;1(1):113-119. on-line reference


c. Aortic aneurysms
An aortic aneurysm is an artery potential rupture that can be life-threatening. An Aortic aneurysm is caused by an imbalance between the synthesis and degradation of extracellular matrices in the aortic wall. Chronic inflammation enhances the matrice degradation. Mesenchymal stem cells have anti-inflammatory and immunosuppressive capacities and are also recruited into damaged tissue. The authors discuss this kind of treatment.
Yamawaki-Ogata A, Hashizume R, Fu XM, Usui A, Narita Y. Mesenchymal stem cells for treatment of aortic aneurysms. World J Stem Cells 2014; 6(3):278-87. on-line reference


d. Hypertension and the Kidneys

Mesenchymal stem cells have shown improvements in the renal parenchyma to improve blood flow. The stem cells also reduced fibrosis, systolic blood pressure and sympathetic nervous system hyperactivity and improved the function of the kidneys.
Oliveira-Sales EB, Varela VA, Bergamaschi CT, Campos RR, Boim MA. Effects of mesenchymal stem cells in renovascular hypertension. Exp Physiol 2015 Jan 21 [Epub ahead of print] on-line reference