By:

Louis A. Cona, MD

Reviewed:

Robert J. Hancock

Mesenchymal stem cells (MSCs) are one of the most researched types of cells for regenerative stem cell-based therapies. This is due to their diversified capabilities that can lead to promising outcomes in a variety of different conditions. This article outlines the three most common sources of mesenchymal stem cells (MSCs) as well as their primary mechanisms of action (how they work).

What are mesenchymal stem cells?

Stem cells are the body's raw materials — cells from which all other cells with specialized functions are created. Mesenchymal stem cells are adult stem cells that have self-renewal, immunomodulatory, anti-inflammatory, signaling, and differentiation properties.  Mesenchymal stem cells (MSCs), self renewal capacity is characterized by their ability to divide and develop into multiple specialized cell types present in a specific tissue or organ. 

Mesenchymal stem cells (MSCs) can be sourced from a variety of tissue including adipose tissue (fat), bone marrow, umbilical cord tissue, blood, liver, dental pulp, and skin.  This article will focus on mesenchymal stem cells that are derived from adipose tissue (ADSCs), bone marrow (BMSCs) & umbilical cord tissue (UC-MSCs).

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Clinical Applications

MSCs are widely used in the treatment of various diseases due to their self-renewable, differentiation, anti-inflammatory, and immunomodulatory properties. In-vitro (performed in a laboratory setting) and in-vivo (taking place in a living organism) studies have supported the understanding mechanisms, safety, and efficacy of MSC therapy in clinical applications. (3)

According to a 2018 study conducted by Crigna, et al.

"MSCs mainly exert their regenerative effects through paracrine and endocrine modes of action, which include immunomodulatory, anti-inflammatory, mitogenic, anti-apoptotic, anti-oxidative stress, anti-fibrotic, and angiogenic influences." (1)

Adipose Tissue-Derived MSCs (ADSCs)

Adipose tissue-derived MSCs are obtained from the subcutaneous adipose tissue (fat tissue), they can be rapidly acquired in large numbers and with high cellular activity through a liposuction procedure (2).  

ADSCs are likely to be more viable when sourced from a younger donor.  This may prove to be an issue with older patients that participate in an autologous procedure (using your cells), as the older cells may be less fitted for long-term survival in the recipient.  Adipose tissue-derived MSCs (ADSCs) from younger donors present a higher proliferation rate (survivability after transplant) when compared to elderly ones, but the differentiation capacity is maintained with aging, thus having advantages on bone marrow mesenchymal stem cells (BM-MSCs).  

However, ADSCs do maintain their potential to differentiate into cells of mesodermal (middle cell layer) origin and they are commonly known for their low immunogenicity and modulatory effects. Less than 1% of them expressed the HLA-DR protein on their surface, leading to immunosuppressive effects and making them suitable for clinical applications in allogeneic transplantation and therapies for the treatment of resistant immune disorders. (2)

It is widely accepted that ADSCs can be used for a variety of different conditions. ADSCs can also be a viable source for most orthopedic treatments.  Common applications may be spinal cord injury, arthritis, localized joint inflammation, knee pain, and other musculoskeletal issues.

However, there are still some challenges that surround the use of ADSCs in a clinical setting.  These challenges include proliferative limitations concerning the age of cells, limited differentiation capabilities, and protocol standardization.  

According to a study published by Mazini et al. 

"ADSCs represent many therapeutic challenges in terms of origin, type, and the manner to use them, different recent investigations pave the way to their successful therapeutic use in tissue repair. More insights into standardizing technical use are warranted to evaluate the in-depth efficacy and safety of ADSCs-based therapy and evaluate the benefit-to-risk ratio in clinical applications. The beneficial effects of stem cells, and there with the paradigm of tissue regeneration, may not be restricted to cellular restoration, but may also be related to the transient paracrine actions of the cells."

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Bone Marrow-Derived MSCs (BM-MSCs)

Bone marrow-derived mesenchymal stem cells (BM-MSCs), which are classified as multipotent adult stem cells, are widely used in the treatment of various diseases via their self-renewable, differentiation, and immunomodulatory properties.  

"In-vitro and in-vivo studies have supported the understanding mechanisms, safety, and efficacy of BM-MSCs therapy in clinical applications. The number of clinical trials in phase I/II is accelerating; however, they are limited in the size of subjects, regulations, and standards for the preparation and transportation, and administration of BMSCs, leading to inconsistency in the input and outcome of the therapy." (3)

Limitations‍

Bone Marrow harvesting is a highly invasive and painful procedure that requires general anesthesia and multiple days for hospital care. BM-MSCs constitute a rare population, with only 0.002% of the total stromal (stem) cell population, and their isolation depends on the patient status and the volume of matter collected. (2)

Similar to ADSCs bone marrow stem cell's quantity and quality decline with age.  BM-MSCs are likely to be more viable when sourced from a younger donor when employing an allogeneic (cells come from a third party) treatment.  This may prove to be an issue with older patients that participate in an autologous procedure, as the older cells may be less fitted for long-term survival in the recipient.  This issue is outlined by Chu et al. in a 2020 study.  

"Stem cells that were isolated from elders had a low rate of proliferation and differentiation ability into osteoblasts, whereas they increase the expression of apoptosis markers and SA-β-gal positive cells (an indicator of the senescence cells)" (3)

Most of the preclinical and clinical trials have shown promising results of BMSCs on the treatments of various diseases with few adverse effects during follow-up periods. Currently, BM-MSCs therapy has been used in the treatment of osteoarthritis, neurodegenerative diseases, and sports-related injuries. (3)

Umbilical Cord Tissue-Derived Mesenchymal Stem Cells (UC-MSCs)

UC-MSCs can be sourced from a variety of areas including Wharton’s Jelly, cord lining, and peri-vascular region of the umbilical cord. As a commonly discarded tissue, the umbilical cord contains a rich source of mesenchymal stromal cells, which are therefore obtained non-invasively (14). 

"UC-MSCs are the most primitive type of MSCs, shown by their higher expression of Oct4, Nanog, Sox2, and KLF4 markers." (1) 

Umbilical cord tissue-derived mesenchymal stem cells have the ability to differentiate into different cell types and have the greatest proliferation rate of the three mentioned types of stem cells (adipose, bone marrow, cord tissue). (2)

Similar to adipose tissue and bone marrow-derived MSCs, UC-MSCs are known to secrete growth factors, cytokines, and chemokines, improving different cell repair mechanisms. (4). These functions all assist the anti-inflammatory and immunomodulatory properties of MSCs.

Non-invasive cell product

The harvesting procedure of UC-MSCs is non-invasive as it does not require extraction from the patient.  The MSCs are taken directly from an area of an ethically donated human umbilical cord. 

UC-MSCs also have a high proliferative potential than BMSCs and ASCs meaning they expand in vitro more effectively allowing for greater efficiency when obtaining higher cell numbers. (15)

Studies have found that UC-MSCs genes related to cell proliferation (EGF), PI3K-NFkB signaling pathway (TEK), and neurogenesis (RTN1, NPPB, and NRP2) were upregulated (increase in the number of receptors) in UC-MSCs compared to in BM-MSCs. (15)

The image below shows a comparison between BMSCs, ADSCs, and UC-MSCs.  

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How do mesenchymal stem cells work in the body?

Mesenchymal stem cells utilize their self-renewal, immunomodulatory, anti-inflammatory, signaling, and differentiation properties to influence positive change within the body.  Mesenchymal stem cells (MSCs) also have the capacity to self-renew by dividing and developing into multiple specialized cell types present in a specific tissue or organ.  Mesenchymal stem cells are adult stem cells, meaning they present no ethical concerns, MSCs are not sourced from embryonic material.

"The characteristics of presenting no major ethical concerns, having low immunogenicity, and possessing immune modulation functions make MSCs promising candidates for stem cell therapies." - Jiang, et al. (6)

Immunomodulatory (regulating the immune system)

Mesenchymal stem cells (MSCs) can regulate the immune system by promoting an inflammatory response when the immune system is under-activated and reducing inflammation when the immune system is overactivated.  MSCs can play a key role in preventing the immune system from attacking itself similar to what one may see in many autoimmune disorders.  According to a 2013 study conducted by Bernardo et al. MSCs, when exposed to sufficient levels of pro-inflammatory markers (cytokines) respond by promoting an immune-suppressive response to dampen inflammation and promote tissue homeostasis. (7)

According to a 2019 study conducted by Jiang, et al. 

"Depending on the signal types or strength, MSCs secrete cytokines to promote or suppress the immune responses for maintaining the immune balance."

This balance is outlined by the same study in the figure below.

Figure 2. Table showcasing immune system balance

Anti-inflammatory (reducing harmful inflammation)

Inflammation is a response from the immune system that is aimed at protecting the body from harmful external stimuli as well as aid and repair the body.  However, when dysregulated inflammation can have a detrimental effect on the body.  An immune system that is dysregulated for an extended period can lead to a variety of autoimmune conditions such as Multiple Sclerosis, Type 1 Diabetes, Inflammatory Bowel Disease, or Lupus. (8)

The anti-inflammatory properties of MSCs play a key role in their therapeutic abilities.  

How MSCs reduce inflammation

"MSCs from different sources reduce inflammation by decreasing production of tumor necrosis factor-α (TNF-α) and Interferon-γ (IFN-γ) and increasing Prostaglandin (PGE2) and Interleukin-6 (IL-6) secretion." (9) 

According to a 2020 study conducted by Gugjoo et al. 

"In general, the central role of mesenchymal stem cells (MSCs) in maintaining homeostasis (immuno-modulation and anti-inflammatory activities) occurs by interacting with immune cells and is mediated through cytokines, chemokines, cell surface molecules, and metabolic pathways. MSCs suppress T-cell proliferation, cytokine secretion, and cytotoxicity (9)"

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MSC secretome and extracellular vesicles (exosome signaling)

The regenerative effects of mesenchymal stem cells do not solely rely on their differentiation potential and ability to replace the injured tissues, but also mediated by their secretome via paracrine mechanisms. (5)

MSC secretome is a set of bioactive factors that are released into the body including cytokines, growth factors, extracellular vesicles, neurotrophins, soluble proteins, lipids, and nucleic acids.  (5)

The secretomes that are released play important roles in the regulation of many physiological processes and they are of increasing interest as potential biomarkers and therapeutic targets in diseases. (10)

According to a 2016 study conducted by Arutyunyan et al. UC-MSCs exhibit increased secretion of neurotrophic factors such as bFGF, nerve growth factor (NGF), neurotrophin 3 (NT3), neurotrophin 4 (NT4), and glial-derived neurotrophic factor (GDNF) compared to bone marrow-derived (BM-MSCs) and adipose tissue-derived (AT-MSCs). (15)

Additionally, UC-MSCs secrete significantly higher amounts of several important cytokines and hematopoietic growth factors, including G-CSF, GM-CSF, LIF, IL-1α, IL-6, IL-8, and IL-11, compared to BM-MSCs.  This suggests that UC-MSCs may be more potent than other sources of MSCs. 

Homing properties (how MSCs know where to go)

One of the key benefits of mesenchymal stem cells is their ability to target specific areas of concern due to their intrinsic homing capabilities.  Mesenchymal stem cell homing, when administered systemically can be defined as exiting circulation and migrating to the injury site. (11)

According to a 2019 study conducted by Ullah et al. 

Systemic homing is a multistep process governed by specific molecular interactions. "The process of systemic homing can be split into five steps: (1) tethering and rolling, (2) activation, (3) arrest, (4) transmigration or diapedesis, and (5) migration". 

This process is outlined in the figure below.

Figure 3. Homing properties of MSCs

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Differentiation (becoming new types of cells)

Mesenchymal stem cells are multipotent stem cells that can self-renew and differentiate into different cell types. In other words, mesenchymal stem cells can become a variety of different cell types including; adipose tissue, cartilage, muscle, tendon/ligament, bone, neurons, and hepatocytes (12)

According to a 2016 study conducted by Almalki et al. -  "The differentiation of MSCs into specific mature cell types is controlled by various cytokines, growth factors, extracellular matrix molecules, and transcription factors (TFs). (12)

Mesenchymal stem cells contribute to tissue regeneration and differentiation, including the maintenance of homeostasis and function, adaptation to altered metabolic or environmental requirements, and the repair of damaged tissue. (13)

Conclusion

There is a plethora of research surrounding the mechanisms of mesenchymal stem cells (MSCs).  Many studies have outlined their diversified capabilities including self-renewal, immunomodulatory, anti-inflammatory, signaling, and differentiation properties.  These characteristics enable MSCs to be used in a variety of clinical settings for multiple degenerative conditions.  

Research is starting to suggest that umbilical cord tissue-derived MSCs (UC-MSCs) may be more potent than other sources of mesenchymal stem cells thus potentially increasing their clinical efficacy. (15)   

To learn more about the use of UC-MSCs in a clinical setting visit our protocol page.  DVC Stem provides an expanded stem cell treatment that utilizes umbilical cord tissue-derived mesenchymal stem cells (UC-MSCs) sourced from an FDA-compliant lab in the United States.  DVC Stem offers treatment for a variety of conditions including Multiple Sclerosis, Crohn's Disease, Parkinson's, and other autoimmune conditions.

Learn more about DVC Stem's protocol here.

References: 

(1) Torres Crigna, A., Daniele, C., Gamez, C., Medina Balbuena, S., Pastene, D. O., Nardozi, D., … Bieback, K. (2018, June 15). Stem/Stromal Cells for Treatment of Kidney Injuries With Focus on Preclinical Models. Frontiers in medicine. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013716/.

(2) Mazini, L., Rochette, L., Amine, M., & Malka, G. (2019, May 22). Regenerative Capacity of Adipose-Derived Stem Cells (ADSCs), Comparison with Mesenchymal Stem Cells (MSCs). International journal of molecular sciences. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566837/.

(3) Chu, D.-T., Phuong, T. N. T., Tien, N. L. B., Tran, D. K., Thanh, V. V., Quang, T. L., … Kushekhar, K. (2020, January 21). An Update on the Progress of Isolation, Culture, Storage, and Clinical Application of Human Bone Marrow Mesenchymal Stem/Stromal Cells. International journal of molecular sciences. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037097/.

(4) Jin, H. J., Bae, Y. K., Kim, M., Kwon, S.-J., Jeon, H. B., Choi, S. J., Kim, S. W., Yang, Y. S., Oh, W., & Chang, J. W. (2013, September 3). Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy. International journal of molecular sciences. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794764/.

(5) Liau, L. L., Looi, Q. H., Chia, W. C., Subramaniam, T., Ng, M. H., & Law, J. X. (2020, September 22). Treatment of spinal cord injury with mesenchymal stem cells. Cell & bioscience. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510077/.

(6) Jiang, W., & Xu, J. (2020, January). Immune modulation by mesenchymal stem cells. Cell proliferation. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985662/.

(7) Bernardo, M. E., & Fibbe, W. E. (2013). Mesenchymal Stromal Cells: Sensors and Switchers of Inflammation. Cell Stem Cell, 13(4), 392–402. https://doi.org/10.1016/j.stem.2013.09.006

(8) Ryu, J.-S., Jeong, E.-J., Kim, J.-Y., Park, S. J., Ju, W. S., Kim, C.-H., Kim, J.-S., & Choo, Y.-K. (2020, November 7). Application of Mesenchymal Stem Cells in Inflammatory and Fibrotic Diseases. International journal of molecular sciences. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664655/.

(9) Gugjoo, M. B., Hussain, S., Amarpal, Shah, R. A., & Dhama, K. (2020). Mesenchymal Stem Cell-Mediated Immuno-Modulatory and Anti- Inflammatory Mechanisms in Immune and Allergic Disorders. Recent patents on inflammation & allergy drug discovery. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509741/.

(10) Stastna, M., & Van Eyk, J. E. (2012, February 1). Investigating the secretome: lessons about the cells that comprise the heart. Circulation. Cardiovascular genetics. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282018/.

(11) Ullah, M., Liu, D. D., & Thakor, A. S. (2019, May 31). Mesenchymal Stromal Cell Homing: Mechanisms and Strategies for Improvement. iScience. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529790/.

(12) Almalki, S. G., & Agrawal, D. K. (2016). Key transcription factors in the differentiation of mesenchymal stem cells. Differentiation; research in biological diversity. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010472/.

(13) Grafe, I., Alexander, S., Peterson, J. R., Snider, T. N., Levi, B., Lee, B., & Mishina, Y. (2018, May 1). TGF-β Family Signaling in Mesenchymal Differentiation. Cold Spring Harbor perspectives in biology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932590/.

(14) Walker, J. T., Keating, A., & Davies, J. E. (2020, May 28). Stem Cells: Umbilical Cord/Wharton’s Jelly Derived. Cell Engineering and Regeneration. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992171/.

(15) Arutyunyan, I., Elchaninov, A., Makarov, A., & Fatkhudinov, T. (2016). Umbilical Cord as Prospective Source for Mesenchymal Stem Cell-Based Therapy. Stem cells international. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019943/.