Please enable JavaScript.
Coggle requires JavaScript to display documents.
The stem cell secretome and it's role in modulating repair and…
The stem cell secretome and it's role in modulating repair and regeneration
What is the stem cell secretome?
Secretome = a portion of cells secreted into the extracellular space (a)
Specific to different cells and tissues (a)
Changes depending on pathology or physiological state (a)
Mesenchymal stem cell secretome includes cytokines, mRNAs, growth factors and active lipids with vital roles in skin tissue regeneration (b) Proteins, nucleic acids, proteasomes, exosomes, mRNA and membrane vesicles (b) Wide range of proteins involved in haemostasis, inflammation and wound repair (b)
wound repair proteins include: growth factors, inflammatory proteins, ECM proteins and angiogenic factors (table 2) (b)
Released in response to the surrounding environment (b) influences neighbouring cells and regulates multiple biological processes (b)
MSCs derived from different organs share phenotypic and regenerative characteristics but, their secretome is different, depending on their origin (b)
Potential applications of the stem cell secretome
Secretome of MSCs derived from different organs are different so, could have different therapeutic potentials (b)
Ref b has a table (table 1) of secretome from MSCs of different organs, the component tested, target and outcome of test
Been shown to have significant positive effects when treating inflammatory disorders of the cardiovascular, skeletal, respiratory and nervous systems (b)
Chronic wound healing (MSC-S)
non-healing wounds cause large economic burden and high morbidity and mortality worldwide (b)
Many wound healing products available but often wounds still fail to heal or heal with scarring so there is a need for alternative wound therapies which promote healing and decrease scar formation (b)
BM-MSC-S injected into margins of excisional wounds in mice promotes wound healing by diminished inflammation mediated by macrophage polymerisation (b)
In preclinical studies, BM-MSC-S treatment improved partial-thickness burn injury repair in rats, mediated by increased blood vessel formation. Another study found topical administration of BM-MSC-S cream to full-thickness burns in rats resulted in increased numbers of fibroblasts, improved angiogenesis and accelerated wound closure. Sub-cutaneous injection of umbilical cord-derived MSC-S to wounds of diabetic mice caused accelerated wound-closure and high capillarity density in wound areas (b)
Treatment with MSC-S significantly accelerates new tissue formation, collagen deposition and re-epithelialisation in treated wounds. A study found topical treatment of ADSC-S to excisional wounds in rats lead to accelerated wound closure and faster re-epithelialisation (b)
Modification of MSCs could improve the therapeutic use of their secretome - look at ref c
Autoimmune disease
Immunosuppressive properties of MSC-S have been hypothesised to be one of the main mechanisms of action of MSC-S when treating autoimmune disease (b)
Components of the stem cell secretome and their functions
Anti-inflammatory/immunomodulatory
MSC-secreted cytokines
Interactions between MSCs and immune cells can be attributed to MSC-secreted cytokines (b)
Interleukin-1 receptor antagonist (IL1-RA) inhibits B cell differentiation (b)
Galectin-1 has inhibitory impacts on proliferation of alloreactive CD4+ and CD8+ T cells (b)
Programmed death-ligand 1(PDL1) supresses T cell activation and increases T cell apoptosis (b)
Prostaglandin E2 (PGE2), TGF-β1, IL-6 and Nitric Oxide provide inhibitory effects on T cells, neutrophils, macrophages and natural killer cells (b)
MSC-S as a whole has been shown to exert immunosuppressive effects through modulating proliferation and activation of immune cells (b)
Increased angiogenesis
One of the main mechanisms of action of the MSC-S (b)
Suggested that it is mediated by secretion of Cyr61 from MSCs (b)
Pro-angiogenic proteins secreted by MSCs also contribute to vascular formation and stability including Ang-1, Ang-2, VEGF, angiostatin, CXCL16, EGF, FGF, PDGF, granulocyte-macrophage colony-stimulating factor (GM-CSF) HGF, MCP-1, MMP-8 and MMP-9 (b)
Improve Extracellular Matrix production and remodelling
MSC-S from different origins enhance migratory and proliferative abilities of dermal fibroblasts (b)
Adipose tissue-derived MSC-S has been shown to protect dermal fibroblasts from oxidative stress-mediated apoptosis and accelerate wound closure with stimulatory effects on fibroblast migration (b)
Accelerate re-epithelisation
MSC-S from different origins enhance migratory and proliferative abilities of epidermal keratinocytes (b)
Alters expression of genes involved in re-epithelialisation (b)
Beneficial effect of MSC-S on skin cells is believed to be mediated by growth factors including IGF-1, EGF, FGF-2, KGF, TGF-β, HGF, PDGF, VEGF, SDF-1 and erythropoietin, and chemokines including IL-6, IL-8, MCP-1 and RANTES)
Anti-apoptotic activity
look at ref c
Neuroprotective and neurotrophic
look at ref c
Antitumor effect
look at ref c
Anti-fibrotic activity
look at ref f
Anti-catabolic
look at ref f
pro-chondrogenic
look at ref f
Discussion
Alternatives to stem cell seceretome therapies
MSC Cell Therapy
MSCs are immune privileged so can be given to donors without fear of rejection (I think that's what that means?) (b)
Cell based skin graft substitutes - expensive, require specific storage condtions, potential risk of tumorogenicity, infection and rejection and difficult to use (b)
Recombinant growth factors - significant amounts needed for effective treatment, expensive to manufacture, lack of clinically relevant improvements in healing (b)
Deliver only one or two specific proteins to the wound, wounds are complex environments and multiple factors may be needed to stimulate healing (b)
MSCs from different origins have different secretomes thus, different therapeutic potentials
Advantages of Secretome therapy
The MSC-S contains a vast array of proteins at physiological and balanced levels including cytokines, growth factors and chemokines, make it potentially a superior alternative to expensive cytokine and chemokine therapies which only administer one or two proteins to the wound (b)
Avoids the difficulties of administering live cells (can elicit an immune response, cells injected through a needle have decreased viability and can damage the cell membrane) (b)
Ease of mass production, packaging and transportation (b)
Challenges of Secretome therapy
Secretome Characterisation
Identifcation and characterisation of all the biomolecules constituting the secretome is difficult but will improve understanding of secreted factor profile and find out function, regulation and clinical use (b)
Mechanism of action of the MSC-S must be elucidated before it can be widely introduced as a potential new therapy (b)
Inconsistency in preparation of secretome
Inconsistency in secretome harvesting in terms of MSC heterogeneity, inter-donor differences, cell number and time interval (b)
Potential side effects
There are always potential risks when using exogenous biological molecules however, these risks are reduced compared to using cell-based therapies (b)
Immunosuppressive properties - may diminish the immune system which may increase risk of infection, immunodeficiency and tumour growth in treated patients so, an optimal amount should be defined to find a balance between safety and effectiveness (b)
Limitation of secretome resources
Number of MSCs required to produce sufficient quantities of secretome for an equivalent number of acute wounds is about 10-25 times higher than directly administered live cells. This challenge could be minimised by increased production and improvement in cell factories and bioreactors.
Can address this challenge by preconditioning cells to stimulate the paracrine production of the secretome (b)
Instability and short half-life of secretome components
Preconditioning cells
Precondition cells to stimulate paracrine production of the stem cell to decrease number of MSCs required (b)
Can control the composition of the secretome to avoid toxicity caused by upregulated cytokines. First elevate production of desirable factors and downregulate detrimental ones. Can also achieve a balance of stimulatory and inhibitory factors. (b)
Different pre-treatment methods including subjecting stem cells to hypoxia or anoxia has been reported to increase production of cytokines and growth factors in transplanted stem cells. (b)
Genetic manipulation of cells using transgenes can also alter specific gene expression with the aim of controlling the MSC-S post-transplantation. (b)
Can pre-treat stem cells with small molecules including inflammatory cytokines and growth factors. Treating MSCs with inflammatory cytokines increases their secretion of anti-inflammatory biomolecules and improves their immunosuppressive functions. (b)
Preconditioning through cell-cell interactions can improve secretion of favourable biomolecules (b)
Tailoring of the MSC-S could lead to numerous off the shelf products specifically designed for treatment of specific conditions or wound types. (b)