Heterogeneity of In Vitro Expanded Mesenchymal Stromal Cells and Strategies to Improve Their Therapeutic Actions

Olmedo-Moreno, Laura; Aguilera, Yolanda; Baliña-Sánchez, Carmen; Martín-Montalvo, Aléjandro; Capilla-González, Vivian

doi:10.3390/pharmaceutics14051112

Cited by 27 publications

(22 citation statements)

References 172 publications

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“…Essential part of performed studies administered MSCs in combination with biomaterials and biomolecules, that masked therapeutic effect of cells. An additional factor may have been the lack of predictive methods and quantitative approaches in the planning of cell therapies ( 27 , 101 , 102 ).…”

Section: Discussionmentioning

confidence: 99%

“…Cell transformation in culture (change in morphology, growth inhibition, aberrations) Cells are capable of transforming in culture due to modification of their regulatory activity by growth factors, cell medium, adhesion, and intercellular connections. Culture-expanded MSCs exhibit notable differences in terms of cell morphology, physiology, and function, which decisively contribute to the heterogeneity of MSC's (27). The heterogeneity of MSCs during in vitro expansion led to morphological alterations, modifications in the gene and protein expression profile, discrepancies in the differentiation potential, and physiological changes in cells (28,29) The majority of cell cultures are characterized by heterogeneity in subpopulations due to the influence of multiple factors arising during protocol reproduction.…”

Section: Minor Side Effectsmentioning

confidence: 99%

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Adverse events, side effects and complications in mesenchymal stromal cell-based therapies

Baranovskii¹,

Klabukov²,

Arguchinskaya³

et al. 2022

Stem Cell Investig

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Numerous clinical studies have shown a wide clinical potential of mesenchymal stromal cells (MSCs) application. However, recent experience has accumulated numerous reports of adverse events and side effects associated with MSCs therapy. Furthermore, the strategies and methods of MSCs therapy did not change significantly in recent decades despite the clinical impact and awareness of potential complications.An extended understanding of limitations could lead to a wider clinical implementation of safe cell therapies and avoid harmful approaches. Therefore, our objective was to summarize the possible negative effects observed during MSCs-based therapies. We were also aimed to discuss the risks caused by weaknesses in cell processing, including isolation, culturing, and storage. Cell processing and cell culture could dramatically influence cell population profile, change protein expression and cell differentiation paving the way for future negative effects. Long-term cell culture led to accumulation of chromosomal abnormalities.Overdosed antibiotics in culture media enhanced the risk of mycoplasma contamination. Clinical trials reported thromboembolism and fibrosis as the most common adverse events of MSCs therapy. Their delayed manifestation generally depends on the patient's individual phenotype and requires specific awareness during the clinical trials with obligatory inclusion in the patient' informed consents. Finally we prepared the safety checklist, recommended for clinical specialists before administration or planning of MSCs therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Minor Side Effectsmentioning

confidence: 99%

Adverse events, side effects and complications in mesenchymal stromal cell-based therapies

Baranovskii¹,

Klabukov²,

Arguchinskaya³

et al. 2022

Stem Cell Investig

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“…iPSCs), thus overcoming the availability limitation for the manufacturing process ( 45 ). Moreover, while tissue-derived MSCs possess high heterogeneity that may interfere with their therapeutic effects ( 25 ), iMSCs are theoretically more homogeneous because they can generate from a single iPSC clone ( 26 , 27 ). Consequently, iMSCs may yield more consistent and reproducible results, even when different batches of iMSCs are used.…”

Section: Discussionmentioning

confidence: 99%

“…In this context, the use of iPSCs as an unlimited source of MSCs (i.e., iMSCs) emerges as an interesting option that enables large-scale production of cellular products for both autologous and allogenic therapies. Furthermore, iMSCs can generate from a single iPSC clone, thus reducing the heterogeneity acquired by tissue-derived MSCs ( 25 – 27 ). These attributes facilitate the obtaining of consistent and robust final products that could be used for the prevention of radiation-related neurological complications.…”

Section: Introductionmentioning

confidence: 99%

Generation of mesenchymal stromal cells from urine-derived iPSCs of pediatric brain tumor patients

et al. 2023

Self Cite

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Human induced pluripotent stem cells (iPSCs) provide a virtually inexhaustible source of starting material for next generation cell therapies, offering new opportunities for regenerative medicine. Among different cell sources for the generation of iPSCs, urine cells are clinically relevant since these cells can be repeatedly obtained by non-invasive methods from patients of any age and health condition. These attributes encourage patients to participate in preclinical and clinical research. In particular, the use of urine-derived iPSC products is a convenient strategy for children with brain tumors, which are medically fragile patients. Here, we investigate the feasibility of using urine samples as a source of somatic cells to generate iPSC lines from pediatric patients with brain tumors (BT-iPSC). Urinary epithelial cells were isolated and reprogrammed using non-integrative Sendai virus vectors harboring the Yamanaka factors KLF4, OCT3/4, SOX2 and C-MYC. After reprogramming, BT-iPSC lines were subject to quality assessment and were compared to iPSCs obtained from urine samples of non-tumor pediatric patients (nonT-iPSC). We demonstrated that iPSCs can be successfully derived from a small volume of urine obtained from pediatric patients. Importantly, we showed that BT-iPSCs are equivalent to nonT-iPSCs in terms of morphology, pluripotency, and differentiation capacity into the three germ layers. In addition, both BT-iPSCs and nonT-iPSCs efficiently differentiated into functional mesenchymal stem/stromal cells (iMSC) with immunomodulatory properties. Therefore, this study provides an attractive approach to non-invasively generate personalized iMSC products intended for the treatment of children with brain tumors.

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“…As discussed by Olmedo-Moreno et al [ 46 ] the heterogeneity in the donor age and co-morbidities can influence the chondrogenic potential of the MSCs [ 46 ]. This heterogeneity may be compounded by the differences in protocols used to isolate and expand the MSCs.…”

Section: Discussionmentioning

confidence: 99%

Evaluating the Effect of Hypoxia on Human Adult Mesenchymal Stromal Cell Chondrogenesis In Vitro: A Systematic Review

Ranmuthu

Wijewardena

et al. 2022

IJMS

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Human adult mesenchymal stromal cells (MSCs) from a variety of sources may be used to repair defects in articular cartilage by inducing them into chondrogenic differentiation. The conditions in which optimal chondrogenic differentiation takes place are an area of interest in the field of tissue engineering. Chondrocytes exist in vivo in a normally hypoxic environment and thus it has been suggested that exposing MSCs to hypoxia may also contribute to a beneficial effect on their differentiation. There are two main stages in which MSCs can be exposed to hypoxia, the expansion phase when cells are cultured, and the differentiation phase when cells are induced with a chondrogenic medium. This systematic review sought to explore the effect of hypoxia at these two stages on human adult MSC chondrogenesis in vitro. A literature search was performed on PubMed, EMBASE, Medline via Ovid, and Cochrane, and 24 studies were ultimately included. The majority of these studies showed that hypoxia during the expansion phase or the differentiation phase enhances at least some markers of chondrogenic differentiation in adult MSCs. These results were not always demonstrated at the protein level and there were also conflicting reports. Studies evaluating continuous exposure to hypoxia during the expansion and differentiation phases also had mixed results. These inconsistent results can be explained by the heterogeneity of studies, including factors such as different sources of MSCs used, donor variability, level of hypoxia used in each study, time exposed to hypoxia, and differences in culture methodology.

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Heterogeneity of In Vitro Expanded Mesenchymal Stromal Cells and Strategies to Improve Their Therapeutic Actions

Cited by 27 publications

References 172 publications

Adverse events, side effects and complications in mesenchymal stromal cell-based therapies

Adverse events, side effects and complications in mesenchymal stromal cell-based therapies

Generation of mesenchymal stromal cells from urine-derived iPSCs of pediatric brain tumor patients

Evaluating the Effect of Hypoxia on Human Adult Mesenchymal Stromal Cell Chondrogenesis In Vitro: A Systematic Review

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