Biological activity of mesenchymal stem cells secretome as a basis for cell-free therapeutic approach

Pokrovskaya, Liubov; Zubareva, E. V.; Nadezhdin, Sergey; Lysenko, Anna S.; Litovkina, Tatyana L.

doi:10.3897/rrpharmacology.6.49413

Cited by 24 publications

(19 citation statements)

References 119 publications

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“…In this study, we harnessed the reparative, regenerative and immunomodulatory potential of MSCs-secretome to promote proper vascular growth in ischemic retinas and prevent pathological neovascular formation. Several studies have shown that the therapeutic effects of MSCs can be associated with soluble paracrine factors and show even better tissue repair than the cells themselves ( Uemura et al, 2006 ; Timmers et al, 2011 ; Liang et al, 2014 ; Pankajakshan and Agrawal, 2014 ; Pokrovskaya et al, 2020 ). MSCs-secretome has shown a low risk of toxicity, and immune rejection ( Baek et al, 2019 ) making it a promising therapeutic alternative for the treatment of IRs.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stromal Cells Promote Retinal Vascular Repair by Modulating Sema3E and IL-17A in a Model of Ischemic Retinopathy

Noueihed

Rivera

Dabouz

et al. 2021

Front. Cell Dev. Biol.

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Ischemic retinopathies (IRs), such as retinopathy of prematurity and diabetic retinopathy, are characterized by an initial phase of microvascular degeneration that results in retinal ischemia, followed by exaggerated pathologic neovascularization (NV). Mesenchymal stromal cells (MSCs) have potent pro-angiogenic and anti-inflammatory properties associated with tissue repair and regeneration, and in this regard exert protection to neurons in ischemic and degenerative conditions; however, the exact mechanisms underlying these functions remain largely unknown. Class III Semaphorins (A–G) are particularly implicated in regulating neural blood supply (as well as neurogenesis) by suppressing angiogenesis and affecting myeloid cell function; this is the case for distinct neuropillin-activating Sema3A as well as PlexinD1-activating Sema3E; but during IR the former Sema3A increases while Sema3E decreases. We investigated whether retinal vascular repair actions of MSCs are exerted by normalizing Semaphorin and downstream cytokines in IR. Intravitreal administration of MSCs or their secretome (MSCs-conditioned media [MSCs-CM]) significantly curtailed vasoobliteration as well as aberrant preretinal NV in a model of oxygen-induced retinopathy (OIR). The vascular repair effects of MSCs-CM in the ischemic retina were associated with restored levels of Sema3E. Vascular benefits of MSCs-CM were reversed by anti-Sema3E; while intravitreal injection of anti-angiogenic recombinant Sema3E (rSema3E) in OIR-subjected mice reproduced effects of MSCs-CM by inhibiting as expected preretinal NV but also by decreasing vasoobliteration. To explain these opposing vascular effects of Sema3E we found in OIR high retinal levels, respectively, of the pro- and anti-angiogenic IL-17A and Sema3A-regulating IL-1β; IL-17A positively affected expression of IL-1β. rSema3E decreased concentrations of these myeloid cell-derived pro-inflammatory cytokines in vitro and in vivo. Importantly, IL-17A suppression by MSCs-CM was abrogated by anti-Sema3E neutralizing antibody. Collectively, our findings provide novel evidence by which MSCs inhibit aberrant NV and diminish vasoobliteration (promoting revascularization) in retinopathy by restoring (at least in part) neuronal Sema3E levels that reduce pathological levels of IL-17A (and in turn other proinflammatory factors) in myeloid cells. The ability of MSCs to generate a microenvironment permissive for vascular regeneration by controlling the production of neuronal factors involved in immunomodulatory activities is a promising opportunity for stem cell therapy in ocular degenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal Stromal Cells Promote Retinal Vascular Repair by Modulating Sema3E and IL-17A in a Model of Ischemic Retinopathy

Noueihed

Rivera

Dabouz

et al. 2021

Front. Cell Dev. Biol.

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“…The secretome may even fluctuate in response to various physiological changes and pathological circumstances. In general, MSC secretome is made up of a variety of growth factors, cytokines, and EVs that conferred its tissue repair and regenerative potential, mainly attributed to their capability to stimulate cell proliferation, formation of new blood vessels, and their immunomodulatory effects (Figure 3) [85,86].…”

Section: Secretomementioning

confidence: 99%

“…Stem Cells International (TNF-β1), IL-10, IL-12 p70, IL-13, IL-18 binding protein, IL-25, and IL-27) and proinflammatory cytokines (such as TNFα, interferon γ (IFN-γ), IL-1b, IL-6, IL-8, and IL-9) could be present. The impact of MSC secretome on the inflammatory process is usually governed by the balance of these anti-and proinflammatory cytokines [86]. For example, the destruction of pancreatic cells in autoimmune diabetes mellitus type 1 disease by proinflammatory cytokines, including TNF-α, IFN-γ, and IL-1b, could be reversed by treating the primary islet cells with MSC secretome containing significantly elevated levels of anti-inflammatory cytokines (IL-4 and IL-10), resulted in the prevention of cell apoptosis and improvement in insulin secretion [99].…”

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confidence: 99%

Comparing the Therapeutic Potential of Stem Cells and their Secretory Products in Regenerative Medicine

Foo

Looi²,

Chong

et al. 2021

Stem Cells International

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Cell therapy involves the transplantation of human cells to replace or repair the damaged tissues and modulate the mechanisms underlying disease initiation and progression in the body. Nowadays, many different types of cell-based therapy are developed and used to treat a variety of diseases. In the past decade, cell-free therapy has emerged as a novel approach in regenerative medicine after the discovery that the transplanted cells exerted their therapeutic effect mainly through the secretion of paracrine factors. More and more evidence showed that stem cell-derived secretome, i.e., growth factors, cytokines, and extracellular vesicles, can repair the injured tissues as effectively as the cells. This finding has spurred a new idea to employ secretome in regenerative medicine. Despite that, will cell-free therapy slowly replace cell therapy in the future? Or are these two modes of treatment still needed to address different diseases and conditions? This review provides an indepth discussion about the values of stem cells and secretome in regenerative medicine. In addition, the safety, efficacy, advantages, and disadvantages of using these two modes of treatment in regenerative medicine are also critically reviewed.

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“…Many other inflammatory mediators such as chemokines or growth factors produced by MSCs may exert different actions inside the tumor microenvironment involving both antitumor and pro-tumor activity [38]. The conditioned medium of MSCs contains an enormous quantity of molecules (cytokines, chemokines, hormones and many other factors) with different biological activity that can also work together with exosomes/microvesicles produced by MSCs [39,40]. As reported by Mirabdollahi et al [41], the secretome of umbilical cord-derived mesenchymal cells can have an anticancer effect on MCF-7 tumor cells by inducing apoptosis in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Human Malignant Pleural Mesothelioma Growth by Mesenchymal Stromal Cells

Coccè

Monica

Bonelli

et al. 2021

Cells

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Background: Malignant Pleural Mesothelioma (MPM) is an aggressive tumor that has a significant incidence related to asbestos exposure with no effective therapy and poor prognosis. The role of mesenchymal stromal cells (MSCs) in cancer is controversial due to their opposite effects on tumor growth and in particular, only a few data are reported on MSCs and MPM. Methods: We investigated the in vitro efficacy of adipose tissue-derived MSCs, their lysates and secretome against different MPM cell lines. After large-scale production of MSCs in a bioreactor, their efficacy was also evaluated on a human MPM xenograft in mice. Results: MSCs, their lysate and secretome inhibited MPM cell proliferation in vitro with S or G0/G1 arrest of the cell cycle, respectively. MSC lysate induced cell death by apoptosis. The efficacy of MSC was confirmed in vivo by a significant inhibition of tumor growth, similar to that produced by systemic administration of paclitaxel. Interestingly, no tumor progression was observed after the last MSC treatment, while tumors started to grow again after stopping chemotherapeutic treatment. Conclusions: These data demonstrated for the first time that MSCs, both through paracrine and cell-to-cell interaction mechanisms, induced a significant inhibition of human mesothelioma growth. Since the prognosis for MPM patients is poor and the options of care are limited to chemotherapy, MSCs could provide a potential new therapeutic approach for this malignancy.

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Biological activity of mesenchymal stem cells secretome as a basis for cell-free therapeutic approach

Cited by 24 publications

References 119 publications

Mesenchymal Stromal Cells Promote Retinal Vascular Repair by Modulating Sema3E and IL-17A in a Model of Ischemic Retinopathy

Mesenchymal Stromal Cells Promote Retinal Vascular Repair by Modulating Sema3E and IL-17A in a Model of Ischemic Retinopathy

Comparing the Therapeutic Potential of Stem Cells and their Secretory Products in Regenerative Medicine

Inhibition of Human Malignant Pleural Mesothelioma Growth by Mesenchymal Stromal Cells

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