Stem cell secretome

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The stem cell secretome (also referred to as the stromal cell secretome) is a collective term for the paracrine soluble factors produced by stem cells and utilized for their inter-cell communication. In addition to inter-cell communication, the paracrine factors are also responsible for tissue development, homeostasis and (re-)generation. The stem cell secretome consists of extracellular vesicles, [1] specifically exosomes, microvesicles, membrane particles, peptides and small proteins (cytokines). The paracrine activity of stem cells, i.e. the stem cell secretome, has been found to be the predominant mechanism by which stem cell-based therapies mediate their effects in degenerative, auto-immune and/or inflammatory diseases. [2] Though not only stem cells possess a secretome which influences their cellular environment, their secretome currently appears to be the most relevant for therapeutic use. [3]

Contents

Extracellular Vesicles

The Extracellular Vesicles are small partials that are normally discharged and have boundaries that are formed by a lipid bilayer. Although cells can replicate, extracellular vesicle is not able to. In the extracellular vesical, things that consist of the stem cell secretome and are being packed are organelles, mRNA, miRNA, and proteins. [4] Exosomes are discharged from the extracellular vesicles, which are found in biological fluid. Biological fluid like the cerebrospinal fluid, which can be used for treatment. Most impotently, exosomes can be found in between the eukaryotic organism's cell, also known as the tissue matrix. [5]

Research

Stem Cell therapies, here referred to as therapies employing non-hematopoietic, mesenchymal stem cells, have a wide range of potential therapeutic benefits for different diseases, most of which are currently investigated in clinical trials. [6] Stem cell therapies can benefit as a regenerative medicine for patients that have or been diagnosed with disease that affect the mid part of the brain, strokes and heart disease, joint disease and injuries to the spinal cord. [7] Therapeutic properties of stem cells are mainly attributed to their secretome, which has been shown to modulate several biological processes in vitro and in vivo, such as cell proliferation, survival, differentiation, immunomodulation, anti-apoptosis, angiogenesis and stimulation of tissue adjacent cells. This is contrary to the historic hypothesis that stem cell migration and transdifferentiation is the primary mechanism of effect of stem cell injection therapies. [2]

The most commonly used type of stem cells for therapeutic use are human (autologous) Mesenchymal Stem Cells, hMSCs. hMSCs’ secretome is one of the most widely researched secretome profile. The secretomes of other cell types, for example dendritic cells, are also being investigated for therapeutic use. [8]

Studies of hMSCs aimed for examining their regenerative capacities for putative treatment of neurodegenerative diseases have demonstrated that hMSCs are able to secrete important neuroregulatory molecules, such as: brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), insulin growth factor 1 (IGF-1), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-β), glial-derived neurotrophic factor (GDNF), fibroblast growth factor 2 (FGF-2), stem cell factor (SCF), granulocyte colony-stimulating factor (G-CSF) and stromal cell-derived factor (SDF-1) both in vitro and in vivo. All of these molecules have been shown to have beneficial effects towards the treatment of neurodegenerative diseases. [9]

With regard to orthopaedic conditions such as arthritis, the paracrine factors of stem cell-based therapies appeared to be responsible for the majority of regenerative effects. Extracellular vesicles have a prominent role in the development of joints and in the regulation of the intra-articular homeostasis. In the case of arthritis, this homeostasis is disrupted due to different reasons. Hypothetically, one reason may be related to the accumulation of senescent cells and their associated secretory phenotype. The secretome of (mesenchymal) Stem Cells have a positive effects on reestablishing the intra-articular homeostasis and stimulating regeneration by different growth factors, cytokines and miRNA that are contained within the extracellular vesicles of the secretome. [10]

As a consequence, efforts have been made to synthesize specific stem cell secretomes efficiently, in vitro. In general, stem cells become activated and produce higher amounts of secretome in response to external stress (for example, by damaged tissues in vivo). As such, the main preconditioning mechanism to induce secretome (extracellular vesicles) production are stress-inducing methods, most prominently anoxia and hypoxia, but also pharmacological, physical or cytokine-related methods that force the cells to produce secretome in vitro. This approach is also known as cell-free stem cell therapy.

It has been hypothesized that future therapies aiming at generating a (specific) secretome with a defined profile, and optimized concentrations of paracrine factors will yield a better, more reliable and controlled outcome as compared to previous approaches that rely solely on injecting (mesenchymal) stem cells into the body and hope that their paracrine (or trans differentiation) capacity will have beneficial effects in the body. [11] However, the controlled therapeutic use of the stem cell secretome demands high-quality standardization of isolation and analysis techniques to yield reproducible secretome preparations.

Various pharmaceutical companies and clinical institutions have started to develop protocols for the in vitro extraction of specific secretome profiles from autologous mesenchymal stem cells, as well as for the clinical use of secretome as a novel therapeutic for numerous diseases, either as a private pay procedure or within clinical trials. [12] [13] Even though these treatments are in compliance with the regulatory framework in Europe under certain conditions as of May 2017, there is yet no evidence for their proven efficacy in human clinical trials, besides singular case reports. Therefore, at the moment, the clinical use of stem cell secretome is experimental, and it is mainly based on in-vitro and animal data. [14] One potential application of autologous stem cell secretome has been in veterinary medicine, as commercialized by a Russian company, T-Helper Cell Technologies in 2017 under the name Reparin-Helper.

Related Research Articles

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

Cell therapy is a therapy in which viable cells are injected, grafted or implanted into a patient in order to effectuate a medicinal effect, for example, by transplanting T-cells capable of fighting cancer cells via cell-mediated immunity in the course of immunotherapy, or grafting stem cells to regenerate diseased tissues.

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.

Stem-cell therapy uses stem cells to treat or prevent a disease or condition. As of 2016, the only established therapy using stem cells is hematopoietic stem cell transplantation. This usually takes the form of a bone marrow transplantation, but the cells can also be derived from umbilical cord blood. Research is underway to develop various sources for stem cells as well as to apply stem-cell treatments for neurodegenerative diseases and conditions such as diabetes and heart disease.

Articular cartilage, most notably that which is found in the knee joint, is generally characterized by very low friction, high wear resistance, and poor regenerative qualities. It is responsible for much of the compressive resistance and load bearing qualities of the knee joint and, without it, walking is painful to impossible. Osteoarthritis is a common condition of cartilage failure that can lead to limited range of motion, bone damage and invariably, pain. Due to a combination of acute stress and chronic fatigue, osteoarthritis directly manifests itself in a wearing away of the articular surface and, in extreme cases, bone can be exposed in the joint. Some additional examples of cartilage failure mechanisms include cellular matrix linkage rupture, chondrocyte protein synthesis inhibition, and chondrocyte apoptosis. There are several different repair options available for cartilage damage or failure.

<span class="mw-page-title-main">Exosome (vesicle)</span> Membrane-bound extracellular vesicles

Exosomes, ranging in size from 30 to 150 nanometers, are membrane-bound extracellular vesicles (EVs) that are produced in the endosomal compartment of most eukaryotic cells. In multicellular organisms, exosomes and other EVs are found in biological fluids including saliva, blood, urine and cerebrospinal fluid. EVs have specialized functions in physiological processes, from coagulation and waste management to intercellular communication.

Neural tissue engineering is a specific sub-field of tissue engineering. Neural tissue engineering is primarily a search for strategies to eliminate inflammation and fibrosis upon implantation of foreign substances. Often foreign substances in the form of grafts and scaffolds are implanted to promote nerve regeneration and to repair damage caused to nerves of both the central nervous system (CNS) and peripheral nervous system (PNS) by an injury.

<span class="mw-page-title-main">Microvesicle</span> Type of extracellular vesicle

Microvesicles are a type of extracellular vesicle (EV) that are released from the cell membrane. In multicellular organisms, microvesicles and other EVs are found both in tissues and in many types of body fluids. Delimited by a phospholipid bilayer, microvesicles can be as small as the smallest EVs or as large as 1000 nm. They are considered to be larger, on average, than intracellularly-generated EVs known as exosomes. Microvesicles play a role in intercellular communication and can transport molecules such as mRNA, miRNA, and proteins between cells.

Mesenchymal stem cells (MSCs) are multipotent cells found in multiple human adult tissues, including bone marrow, synovial tissues, and adipose tissues. Since they are derived from the mesoderm, they have been shown to differentiate into bone, cartilage, muscle, and adipose tissue. MSCs from embryonic sources have shown promise scientifically while creating significant controversy. As a result, many researchers have focused on adult stem cells, or stem cells isolated from adult humans that can be transplanted into damaged tissue.

Amniotic stem cells are the mixture of stem cells that can be obtained from the amniotic fluid as well as the amniotic membrane. They can develop into various tissue types including skin, cartilage, cardiac tissue, nerves, muscle, and bone. The cells also have potential medical applications, especially in organ regeneration.

<span class="mw-page-title-main">Mesenchymal stem cell</span> Multipotent, non-hematopoietic adult stem cells present in multiple tissues

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, chondrocytes, myocytes and adipocytes.

Adult mesenchymal stem cells are being used by researchers in the fields of regenerative medicine and tissue engineering to artificially reconstruct human tissue which has been previously damaged. Mesenchymal stem cells are able to differentiate, or mature from a less specialized cell to a more specialized cell type, to replace damaged tissues in various organs.

<span class="mw-page-title-main">Tumor microenvironment</span> Surroundings of tumors including nearby cells and blood vessels

The tumor microenvironment is a complex ecosystem surrounding a tumor, composed of cancer cells, stromal tissue and the extracellular matrix. Mutual interaction between cancer cells and the different components of the tumor microenvironment support its growth and invasion in healthy tissues which correlates with tumor resistance to current treatments and poor prognosis. The tumor microenvironment is in constant change because of the tumor's ability to influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.

The secretome is the set of proteins expressed by an organism and secreted into the extracellular space. In humans, this subset of the proteome encompasses 13-20% of all proteins, including cytokines, growth factors, extracellular matrix proteins and regulators, and shed receptors. The secretome of a specific tissue can be measured by mass spectrometry and its analysis constitutes a type of proteomics known as secretomics.

The in vivo bioreactor is a tissue engineering paradigm that uses bioreactor methodology to grow neotissue in vivo that augments or replaces malfunctioning native tissue. Tissue engineering principles are used to construct a confined, artificial bioreactor space in vivo that hosts a tissue scaffold and key biomolecules necessary for neotissue growth. Said space often requires inoculation with pluripotent or specific stem cells to encourage initial growth, and access to a blood source. A blood source allows for recruitment of stem cells from the body alongside nutrient delivery for continual growth. This delivery of cells and nutrients to the bioreactor eventually results in the formation of a neotissue product. 

A cancer-associated fibroblast (CAF) is a cell type within the tumor microenvironment that promotes tumorigenic features by initiating the remodelling of the extracellular matrix or by secreting cytokines. CAFs are a complex and abundant cell type within the tumour microenvironment; the number cannot decrease, as they are unable to undergo apoptosis.

<span class="mw-page-title-main">Shimon Slavin</span> Israeli professor of medicine

Shimon Slavin is an Israeli professor of medicine. He pioneered immunotherapy mediated by allogeneic donor lymphocytes and innovative methods for stem cell transplantation to cure hematological malignancies and solid tumors. He also used hematopoietic stem cells to induce transplantation tolerance to bone marrow and organ allografts.

Craniofacial regeneration refers to the biological process by which the skull and face regrow to heal an injury. This page covers birth defects and injuries related to the craniofacial region, the mechanisms behind the regeneration, the medical application of these processes, and the scientific research conducted on this specific regeneration. This regeneration is not to be confused with tooth regeneration. Craniofacial regrowth is broadly related to the mechanisms of general bone healing.

<span class="mw-page-title-main">Stem cell fat grafting</span>

Stem cellfat grafting is the autotransplantation of adipose-derived stem cells (ADSCs) extracted from fat-abundant donor sites to other areas such as the face, breast, and hip to reconstruct the operative areas into desirable shapes. ADSCs are multipotent stem cells found in adipose tissues, displaying similar differentiation potentials to bone marrow-derived mesenchymal stem cells (BM-MSCs).

Exosomes are small vesicles secreted by cells that play a crucial role in intercellular communication. They contain a variety of biomolecules, including proteins, nucleic acids and lipids, which can be transferred between cells to modulate cellular processes. Exosomes have been increasingly acknowledged as promising therapeutic tool and delivery platforms due to unique biological properties.

  1. Biocompatibility: Exosomes are naturally occurring particles in body, which makes them highly biocompatible and less likely to activate immune response.
  2. Targeting ability: Exosomes are assembled to express specific proteins or peptides, allowing them to target specific cells or tissues.
  3. Natural cargo carries: Exosomes can naturally transport a variety of biomolecules, including proteins, RNA and DNA, which can be used for therapeutic purposes.

References

  1. ↑ Pol, Edwin van der; Böing, Anita N.; Harrison, Paul; Sturk, Augueste; Nieuwland, Rienk (2012-07-01). "Classification, Functions, and Clinical Relevance of Extracellular Vesicles". Pharmacological Reviews. 64 (3): 676–705. doi:10.1124/pr.112.005983. ISSN   0031-6997. PMID   22722893. S2CID   7764903.
  2. 1 2 Teixeira, Fábio G.; Carvalho, Miguel M.; Sousa, Nuno; Salgado, António J. (2013-10-01). "Mesenchymal stem cells secretome: a new paradigm for a central nervous system regeneration?". Cellular and Molecular Life Sciences. 70 (20): 3871–3882. doi:10.1007/s00018-013-1290-8. hdl: 1822/25128 . ISSN   1420-682X. PMC   11113366 . PMID   23456256. S2CID   18640402.
  3. ↑ Mahla RS (2016). "Stem cells application in regenerative medicine and disease threpeutics". International Journal of Cell Biology. 2016 (7): 1–24. doi: 10.1155/2016/6940283 . PMC   4969512 . PMID   27516776.
  4. ↑ Mitchell, Robert; Mellows, Ben; Sheard, Jonathan; Antonioli, Manuela; Kertz, Oliver; Chambers, David; Zeuner, Marie-Theres; E.Tomkins, James; Denecke, Brend; Musante, Luca; Joch, Barbara; Debacq-Chaniaux, Florence; Holthofer, Harry; Ray, Steve; B. Huber, Tobias; Dengiel, Joern; De Coppi, Paolo; Widera, Daruis; Patel, Ketan (2019). "Stem Cell Research & Therapy". 10 (1): 116. doi: 10.1186/s13287-019-1213-1 . PMC   6451311 . PMID   30953537.{{cite journal}}: Cite journal requires |journal= (help)
  5. ↑ Kalluri, Raghu; LeBleu, Valerie S. (2020-02-07). "The biology, function, and biomedical applications of exosomes". Science. 367 (6478): eaau6977. doi:10.1126/science.aau6977. ISSN   0036-8075. PMC   7717626 . PMID   32029601.
  6. ↑ Teixeira, Fábio G.; Panchalingam, Krishna M.; Assunção-Silva, Rita; Serra, Sofia C.; Mendes-Pinheiro, Bárbara; Patrício, Patrícia; Jung, Sunghoon; Anjo, Sandra I.; Manadas, Bruno (2016-06-15). "Modulation of the Mesenchymal Stem Cell Secretome Using Computer-Controlled Bioreactors: Impact on Neuronal Cell Proliferation, Survival and Differentiation". Scientific Reports. 6 (1): 27791. Bibcode:2016NatSR...627791T. doi:10.1038/srep27791. ISSN   2045-2322. PMC   4908397 . PMID   27301770.
  7. ↑ "Frequently asked questions about stem cell research". Mayo Clinic. Retrieved 2021-02-22.
  8. ↑ Jarmalaviciute, Akvile; Pivoriūnas, Augustas (2016). "Neuroprotective properties of extracellular vesicles derived from mesenchymal stem cells". Neural Regeneration Research. 11 (6): 904–5. doi: 10.4103/1673-5374.184480 . PMC   4962579 . PMID   27482210.
  9. ↑ Zhang, Bin; Yeo, Ronne Wee Yeh; Tan, Kok Hian; Lim, Sai Kiang (2016-02-06). "Focus on Extracellular Vesicles: Therapeutic Potential of Stem Cell-Derived Extracellular Vesicles". International Journal of Molecular Sciences. 17 (2): 174. doi: 10.3390/ijms17020174 . PMC   4783908 . PMID   26861305.
  10. ↑ Malda, Jos; Boere, Janneke; Lest, Chris H. A. van de; Weeren, P. René van; Wauben, Marca H. M. (2016). "Extracellular vesicles — new tool for joint repair and regeneration". Nature Reviews Rheumatology. 12 (4): 243–249. doi:10.1038/nrrheum.2015.170. PMC   7116208 . PMID   26729461.
  11. ↑ Salgado, António J.; Gimble, Jeffrey M. (2013-12-01). "Secretome of mesenchymal stem/stromal cells in regenerative medicine". Biochimie. Special section : The Mesenchymal Stem Cell secretome in Regenerative Medicine. 95 (12): 2195. doi:10.1016/j.biochi.2013.10.013. PMID   24210144.
  12. ↑ "Anova IRM Stem Cell Center". anova-irm-stemcell-center.com. 2017.
  13. ↑ "Репарин | Главная страница" (in Russian). Retrieved 2020-01-24.
  14. ↑ Konala, Vijay Bhaskar Reddy; Mamidi, Murali Krishna; Bhonde, Ramesh; Das, Anjan Kumar; Pochampally, Radhika; Pal, Rajarshi (2016-01-01). "The current landscape of the mesenchymal stromal cell secretome: A new paradigm for cell-free regeneration". Cytotherapy. 18 (1): 13–24. doi:10.1016/j.jcyt.2015.10.008. ISSN   1465-3249. PMC   4924535 . PMID   26631828.
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