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Olmedo-Moreno, L.;  Aguilera, Y.;  Baliña-Sánchez, C.;  Martín-Montalvo, A.;  Capilla-González, V. Strategies to Potentiate the Therapeutic Properties of MSCs. Encyclopedia. Available online: https://encyclopedia.pub/entry/24338 (accessed on 13 May 2024).
Olmedo-Moreno L,  Aguilera Y,  Baliña-Sánchez C,  Martín-Montalvo A,  Capilla-González V. Strategies to Potentiate the Therapeutic Properties of MSCs. Encyclopedia. Available at: https://encyclopedia.pub/entry/24338. Accessed May 13, 2024.
Olmedo-Moreno, Laura, Yolanda Aguilera, Carmen Baliña-Sánchez, Alejandro Martín-Montalvo, Vivian Capilla-González. "Strategies to Potentiate the Therapeutic Properties of MSCs" Encyclopedia, https://encyclopedia.pub/entry/24338 (accessed May 13, 2024).
Olmedo-Moreno, L.,  Aguilera, Y.,  Baliña-Sánchez, C.,  Martín-Montalvo, A., & Capilla-González, V. (2022, June 22). Strategies to Potentiate the Therapeutic Properties of MSCs. In Encyclopedia. https://encyclopedia.pub/entry/24338
Olmedo-Moreno, Laura, et al. "Strategies to Potentiate the Therapeutic Properties of MSCs." Encyclopedia. Web. 22 June, 2022.
Strategies to Potentiate the Therapeutic Properties of MSCs
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This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics14051112

Beneficial properties of mesenchymal stromal cells (MSCs) have prompted their use in preclinical and clinical research. Accumulating evidence has been provided for the therapeutic effects of MSCs in several pathologies, including neurodegenerative diseases, myocardial infarction, skin problems, liver disorders and cancer, among others. Although MSCs are found in multiple tissues, the number of MSCs is low, making in vitro expansion a required step before MSC application. However, culture-expanded MSCs exhibit notable differences in terms of cell morphology, physiology and function, which decisively contribute to MSC heterogeneity. The changes induced in MSCs during in vitro expansion may account for the variability in the results obtained in different MSC-based therapy studies, including those using MSCs as living drug delivery systems. 

mesenchymal stem cells cell therapy regenerative medicine cell engineering drug delivery

1. Use of Medium Supplements

There are multiple medium supplements that have shown beneficial effects to improve the proliferative capacity of MSCs. FBS is the most widely used growth supplement for cell cultures, primarily because of their high levels of growth stimulatory factors and low levels of growth inhibitory factors. The use of FBS has been proven to increase the proliferative capabilities of MSCs in a concentration-dependent manner [1]. However, FBS may contain animal derivatives enhancing the risk of zoonotic transmission and immunological reactions during cell therapy. In this context, human platelet preparations, such as platelet lysate or platelet-rich plasma, have emerged as an alternative to the use of non-human serum, favoring the biological safety of MSC therapies [1][2][3]. Importantly, the clonogenic efficiency and proliferative capacity of MSCs was found to be greater when using 5% human platelet lysate as compared to 10% fetal serum, probably due to the high concentration of natural growth factors contained in platelets [3]. However, both fetal serum and human platelet preparations are complex natural products that may vary from lot to lot, even from a single manufacturer, contributing to the heterogeneity of MSC function and influencing the clinical utility of these cells. Recently, the development of chemically defined media is gaining increasing importance as an alternative to isolate and expand human MSCs for clinical application [4][5]. Although studies have shown multiple improvements in the therapeutic properties of MSCs cultured in media with fully characterized ingredients [6], more efforts should be made to further optimize and standardize the use of the chemical-defined medium.
The use of growth factors is a common strategy to increase the proliferative rate of MSCs. Among the most frequently used growth factors are fibroblast growth factor (FGF), epidermal growth factor (EGF), transforming growth factor beta (TGFβ), PDGF or VEGF [7]. Along with increasing proliferation, these factors present other beneficial effects that may contribute to improve the MSC therapeutic properties. For instance, the supplementation of culture media with FGF was found to reduce apoptosis and senescence [8][9][10]. A study demonstrated that the use of PDGF-BB can reverse the defective phenotype of Ad-MSCs derived from diabetic patients by improving their migration, proliferation and fibrinolytic capacity in vitro [11]. Furthermore, the pretreatment of Ad-MSCs with PDGF-BB promoted the homing of transplanted cells in a mouse model of cutaneous wounds, suggesting an improved migration and survival of MSCs in vivo [11]. Another method to potentiate the therapeutic properties of MSCs is the supplementation of media with GlutaMAX. This supplement increases the proliferation rate of cells, as compared to media supplemented with L-glutamine [12]. This beneficial effect may be due to the fact that GlutaMAX supplement provides a more stable L-glutamine, since it appears as a dipeptide, L-alanine-L-glutamine, that does not spontaneously degrade.

2. Preconditioning of MSCs

Several studies have used the preconditioning of MSCs to efficiently promote their therapeutic functions. A recent study demonstrated that the melatonin preconditioning of MSCs promoted bone regeneration in an animal calvaria bone defect model by increasing osteogenic differentiation [13]. In a separate study, MSCs pretreated with melatonin exhibited better effects on recovering the liver function than untreated MSCs by enhancing hepatic engraftment after tail vein injection in a mouse liver fibrosis model [14]. The pretreatment of MSCs with mood stabilizers lithium and valproic acid exerted greater benefits on the motor function than non-preconditioned MSCs after intranasal delivery in a mouse model of Huntington’s disease [15]. In particular, this preconditioning enhanced MSC survival post-transplantation and promoted the expression of neurotrophic factors, including FGF-21, FGF-15, neuron-derived neurotrophic factor (NDNF), neurotrophin 3 (NTF3), growth differentiation factor (GDF)-1, insulin-like growth factor (IGF)-1 and bone morphogenetic protein (BMP)-3 [15]. Another research work demonstrated that hypoxia preconditioning effectively promoted the angiogenic capacity of Ad-MSCs obtained from aged donors, increasing the tissue perfusion when they were intramuscularly injected in mice with ischemic hindlimbs [16]. An improved restoration of the blood flow was also observed in the hindlimb ischemia of mice injected with BM-MSCs cultured under hypoxic conditions [17]. In addition, many studies have demonstrated the beneficial effects of pre-stimulating MSCs with cytokines or growth factors [18]. For instance, IFN-γ pre-stimulation increased the immunosuppression properties of MSCs, resulting in diminished mucosal damage after intraperitoneal injection in experimental colitis models [19]. Similar results were found with IL-1β-primed MSCs, which exhibited the enhanced efficacy to ameliorate the pathological aspects of colitis in mice [20]. Another study demonstrated that FGF-2 priming increased the angiogenic capacity of MSCs seeded in tissue constructs and implanted subcutaneously in the back of mice [21]. In particular, this MSC-induced regenerative effect was mediated by the secretion of hepatocyte growth factor (HGF) and VEGF after FGF-2 stimulation. Another study demonstrated that the pretreatment of MSCs with PDGF-BB enhanced engraftment in a cutaneous wound mouse model after tail vein injection [11].

3. Scaffolds as Structural Supports for MSCs

MSC function depends on multiple conditions, including the environment where they are grown. In order to mimic the natural niche of MSCs, scaffolds have been designed as temporary supports helping to preserve their unique biological behavior and properties. A wide variety of natural and synthetic scaffolds have been successfully used in research [22]. Among natural scaffolds, protein- (e.g., hydrogels, collagen, nanoparticles, fibrin, laminin, etc.) and polysaccharide-based biomaterials (agarose, alginate, hyaluronan, chitosan, cellulose, etc.) are the most commonly used, while synthetic biomaterials are typically made of polymers, such as PDMS [22].
Several reports have used scaffolds in experimental animal models as vehicles to deliver MSCs to the target damaged tissue. A comparative study used different biomaterials to evaluate the retention of transplanted MSCs in a rat model of myocardial infarction [23]. In particular, they used two injectable hydrogels (alginate and chitosan/β-glycerophosphate) and two epicardial patches (alginate and collagen). All these biomaterials increased MSC viability under a hostile milieu and promoted the retention of transplanted cells into the heart [23]. In a recent report, an implantable complex combining collagen and silk fibroin with human umbilical cord MSCs was used to regenerate the cerebral cortex in a canine model of traumatic brain injury (TBI). Animals treated with this combinatorial complex exhibited better brain injury repair than those canines implanted with MSCs alone, as well as a restored gait of hemiplegic limbs after TBI [24]. Another study used polymeric nanofibrils decorated with bovine cartilage-derived decellularized extracellular matrix in combination with MSCs for bone regeneration in a rat osteochondral defect model [25]. The use of this supportive scaffold accelerated chondrogenic differentiation of MSCs, favoring in vivo cartilage regeneration at 12 weeks post-implantation [25].
The use of scaffolds to encapsulate MSCs is another strategy to promote their therapeutic effects, since it confers a protective microenvironment. For instance, MSCs encapsulated in alginate-based scaffolds exhibited improved vascularization in an arteriovenous (AV) loop rat model when examined by histology and microcomputed tomography at 4 weeks post-surgery [26]. Another study showed that MSCs encapsulated within collagen I-hyaluronic acid-based hydrogels display an extended secretion profile of proangiogenic; neuroprotective and immunomodulatory paracrine factors, including VEGF, bFGF and leukemia inhibitory factor (LIF), which favor tissue regeneration [27]. The encapsulation strategy has also been employed to protect transplanted MSCs from the host immune system, which is of special relevance for allogenic cell therapies. Thus, both allogeneic and xenogeneic MSCs that were implanted in immunocompetent rats using a three-dimensional alginate construct persisted for several weeks (i.e., up to 5 weeks post-transplant), while MSCs alone were undetectable after 1 week post-transplant [28]. Importantly, the MSC–alginate constructs preserved their immunomodulatory capacity after long-term in vitro culture by inhibiting T-lymphocyte proliferation and responding to inflammatory stimuli [28]. Therefore, scaffolding can be used as a suitable strategy to potentiate the beneficial effects of MSC-based therapies.

4. MSC Engineering

An increasing number of researchers are using engineering techniques to refine the therapeutic efficacy of MSCs by promoting their homing toward sites of damage, improving cell survival or enhancing the expression and delivery of therapeutic agent [29][30]. One of the most common techniques to modify MSCs is the genetic manipulation using viral and non-viral vectors to induce the expression of different beneficial factors, such as chemokines and their receptors involved in MSC migration. Numerous reports have engineered MSCs to increase the expression of the C-X-C Motif Chemokine Receptor 4 (CXCR4), which binds to stromal cell-derived factor 1 (SDF1), one of the most potent chemoattractant that is overexpressed at injury sites. Thus, enhanced SDF1/CXCR4 signaling may promote the homing of MSCs into damaged areas to boost tissue regeneration. For example, MSCs transduced to express CXCR4 were injected into the tail veins of rats, 24 h after myocardial infarction. CXCR4-overexpressing MSCs were shown to enhance homing into the infarct region of the myocardium and to improve regeneration when compared to non-transduced MSCs [31]. Similar beneficial effects were found when CXCR4-overexpressing MSCs were transplanted in other injury models, such as the TBI mouse model [32], the acute lung injury rat model [33], the rabbit model of intervertebral disc degeneration [34] or the acute kidney injury mouse model [35].
The genetic manipulation of MSCs has also been used to increase the secretion of pro-regenerative proteins. For instance, genetically modified MSCs to overexpress the antiapoptotic gene Bcl-2 displayed greater survival after injection into rat infarcted myocardium, increasing angiogenesis in the infarct zone [36]. In a preclinical study, MSCs overexpressing VEGF induced more rapid and complete restoration of the blood flow in the ischemic limbs of mice compared to non-transduced MSCs [37], similar to that found with E-selectin-overexpressing MSCs [38]. Genetically modified MSCs can also play an important role in antitumor therapies by directly suppressing cancer progression or by acting as carriers of anticancer payloads [39]. Numerous studies have modified MSCs to overexpress cytokines that potentiate immune responses against cancer, such as interleukin (IL)-12, C-X-C Motif Chemokine Ligand 10 (CXCL10), IFN-β or tumor necrosis factor alpha (TNFα) [30], thus reducing tumor growth and improving survival. The BMP-4 has also been used as tumor-suppressing agent in MSC engineering for cancer therapy. In particular, BMP-4-expressing MSCs efficiently suppressed tumor growth and prolonged the survival of glioma-bearing mice [40][41]. Similar anticancer effects were found when MSCs overexpressing the tumor-suppressor gene Phosphatidylinositol 3,4,5-Trisphosphate 3-Phosphatase (PTEN) were administrated in a xenograft glioma mouse model [42]. However, it must be taken into consideration that the use of MSCs in cancer is still controversial, because there is evidence indicating both protumor and antitumor effects, which hamper the translation to the clinic [39]. The performance of meticulous safety studies would be a required step to anticipate the possible risks of a new cell product during oncological treatment. In line with this, a research group rightly evaluated the possible adverse effects of repeated intranasal MSC administration in mice from early after weaning to adult life [43]. After exhaustive in vivo and ex vivo analyses, they discarded the safety issues of intranasally delivered MSCs in both the short and long term. This report, together with a previous efficacy study, brings new perspectives to face future MSC-based therapies in oncology [43][44].
Despite viral vectors are the most common tool used to genetically modify MSCs with high efficiency, and they clinical application have been limited by the high cost of cell production and safety concerns associated with toxicity, immunogenicity and tumorigenicity [45]. In contrast, nonviral vectors offer a safer option but with a low transfection efficiency [45]. Therefore, the development and optimization of safe and effective gene delivery methods is a major challenge for genetic engineering of MSCs. In this context, emerging reports are using the CRISPR-Cas system to improve the therapeutic potential of stem cells [46]. For example, a study used CRISPR-based technology to improve the therapeutic functions of human MSCs in diabetic wound healing by increasing the secretion of different factors, such as PDGF-BB and VEGFA [47]. More recently, a report used the CRISPR-Cas system to engineer Brain-Derived Neurotrophic Factor (BDNF)-overexpressing MSCs that were applied to effectively treat Rett syndrome in an experimental mouse model [48].
The incorporation of therapeutic cargos into MSCs through cellular internalization or cell surface anchoring is another technique to improve the MSC therapeutic properties [29]. In fact, the use of engineered MSCs as drug delivery systems has emerged as a promising approach for biomedical applications. As MSCs migrate to the target tissue, they deliver their cargo to exert local therapeutic effects, minimizing off-target accumulation and adverse reactions. Among the various types of cargos, drugs, nucleic acids, peptides or nanoparticles are the most frequent in MSC-based therapies. Loading MSCs with therapeutic agents has been particularly used in cancer therapy, where microRNAs (miRNAs) [49][50][51][52], oncolytic viruses [53][54][55] or anticancer drugs [56][57] have shown to be effective against cancer. As an example, a recent study modified the cell surface of MSCs with doxorubicin-encapsulated liposomes and evaluated their therapeutic application in subcutaneous tumor-bearing mice and in a lung metastasis mouse model [58]. Doxorubicin, a common anticancer agent, was efficiently delivered from MSCs and suppressed tumor growth [58]. The field of living drug delivery systems is growing fast and will enable the development of new and more effective forms of therapy for different diseases, improving patient health.

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Subjects: Cell & Tissue Engineering
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Laura Olmedo-Moreno
,
Yolanda Aguilera
,
Carmen Baliña-Sánchez
,
Alejandro Martín-Montalvo
,
Vivian Capilla-González
View Times: 243
Revisions: 2 times (View History)
Update Date: 24 Jun 2022
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