Stem cell secretome

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]

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.[4] The 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 the most widely researched secretome profile. The secretomes of other cell types, for example dendritic cells, are also being investigated for therapeutic use.[5]

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.[6]

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 has 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.[7]

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.[8] 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.[9][10] 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.[11] 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.

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.
  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. PMID 23456256.
  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.CS1 maint: uses authors parameter (link)
  4. 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. doi:10.1038/srep27791. ISSN 2045-2322. PMC 4908397. PMID 27301770.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. "Anova IRM Stem Cell Center". anova-irm-stemcell-center.com. 2017.
  10. "Репарин | Главная страница" (in Russian). Retrieved 2020-01-24.
  11. 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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