The issue of heterogeneity of MSC-based advanced therapy medicinal products–a review

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: July 26, 2024

Mesenchymal stromal stem cells (MSCs) possess a remarkable potential for numerous clinical applications due to their unique properties including self-renewal, immunomodulation, paracrine actions and multilineage differentiation. However, the translation of MSC-based Advanced Therapy Medicinal Products (ATMPs) into clinic has frequently met with inconsistent outcomes. One suspected reasons this issue is inherent extensive variability that exists among such ATMPs, which makes interpretation efficacy difficult assess, as well compare results various studies. This stems from differences in tissue sources, donor attributes, variances manufacturing protocols, modes administration. MSCs can be isolated tissues bone marrow, umbilical cord, adipose others, each its phenotypic functional characteristics. While different sources do share common features, they also exhibit distinct gene expression profiles properites. Donor-specific factors age, sex, body mass index, underlying health conditions influence MSC phenotype, morphology, differentiation function. Moreover, variations preparation products introduces additional heterogeneity result cell culture media composition, presence or absence added growth factors, use serum supplements culturing techniques. Once are formulated, storage protocols play pivotal role efficacy. Factors affect viability include concentration, delivery solution importantly, post-thawing where applicable. Ensuing, administration critically distribution functionallity administered cells. As therapies continue advance through trials, implication strategies reduce product imperative. Central addressing these challenges need precise prediction responses, require well-defined populations harmonized assessment specific functions. By issues by meaningful approaches, as, e.g., pooling, field overcome barriers towards more consistent effective therapies.

Language: Английский

---

Therapeutic Perspectives for Inflammation and Senescence in Osteoarthritis Using Mesenchymal Stem Cells, Mesenchymal Stem Cell-Derived Extracellular Vesicles and Senolytic Agents

Cells, Journal Year: 2023, Volume and Issue: 12(10), P. 1421 - 1421

Published: May 18, 2023

Osteoarthritis (OA) is the most common cause of disability worldwide among elderly. Alarmingly, incidence OA in individuals less than 40 years age rising, likely due to increase obesity and post-traumatic osteoarthritis (PTOA). In recent years, a better understanding underlying pathophysiology OA, several potential therapeutic approaches targeting specific molecular pathways have been identified. particular, role inflammation immune system has increasingly recognized as important variety musculoskeletal diseases, including OA. Similarly, higher levels host cellular senescence, characterized by cessation cell division secretion senescence-associated secretory phenotype (SASP) within local tissue microenvironments, also linked its progression. New advances field, stem therapies senolytics, are emerging with goal slowing disease Mesenchymal stem/stromal cells (MSCs) subset multipotent adult that demonstrated modulate unchecked inflammation, reverse fibrosis, attenuate pain, potentially treat patients Numerous studies MSC extracellular vesicles (EVs) cell-free treatments comply FDA regulations. EVs, exosomes microvesicles, released numerous types playing critical cell–cell communication age-related Treatment strategies for being developed target senescent paracrine autocrine secretions SASP. This article highlights encouraging or MSC-derived products alone combination senolytics control patient symptoms mitigate progression We will explore application genomic principles study discovery phenotypes can motivate more precise patient-driven treatments.

Language: Английский

---

Inter‐laboratory multiplex bead‐based surface protein profiling of MSC‐derived EV preparations identifies MSC‐EV surface marker signatures

Journal of Extracellular Vesicles, Journal Year: 2024, Volume and Issue: 13(6)

Published: June 1, 2024

Abstract Mesenchymal stromal cells (MSCs) are promising regenerative therapeutics that primarily exert their effects through secreted extracellular vesicles (EVs). These EVs – being small and non‐living easier to handle possess advantages over cellular products. Consequently, the therapeutic potential of MSC‐EVs is increasingly investigated. However, due variations in MSC‐EV manufacturing strategies, products should be considered as highly diverse. Moreover, diverse array EV characterisation technologies used for further complicates reliable interlaboratory comparisons published data. this study aimed establish a common method can easily by various researchers characterise preparations facilitate comparisons. To end, we conducted comprehensive inter‐laboratory assessment using novel multiplex bead‐based flow cytometry assay panel. This involved 11 different from five laboratories with varying MSC sources, culture conditions, preparation methods. Through panel covering range mostly MSC‐related markers, identified set cell surface markers consistently positive (CD44, CD73 CD105) or negative (CD11b, CD45 CD197) on all explored preparations. Hierarchical clustering analysis revealed distinct marker profiles associated specific processes laboratory conditions. We propose CD73, CD105 CD44 robust minimally identifying MSC‐derived CD11b, CD14, CD19, CD79 markers. Additionally, highlight influence medium components, particularly human platelet lysate, profiles, underscoring conditions resulting standardisable approach profiling offers tool routine manufactured pre‐clinical clinical research, enhances quality control preparations, hopefully paves way higher consistency reproducibility emerging field.

Language: Английский

---

Cellular expansion of MSCs: Shifting the regenerative potential

Aging Cell, Journal Year: 2022, Volume and Issue: 22(1)

Published: Dec. 19, 2022

Mesenchymal-derived stromal or progenitor cells, commonly called "MSCs," have attracted significant clinical interest for their remarkable abilities to promote tissue regeneration and reduce inflammation. Recent studies shown that MSCs' therapeutic effects, originally attributed the cells' direct differentiation capacity into of interest, are largely driven by biomolecules cells secrete, including cytokines, chemokines, growth factors, extracellular vesicles containing miRNA. This secretome coordinates upregulation endogenous repair immunomodulation in local microenvironment through crosstalk MSCs with host cells. Therapeutic applications secretome-derived products often involve vitro monolayer expansion. However, consecutive passaging significantly alters potential, inducing a broad shift from pro-regenerative pro-inflammatory phenotype. A consistent by-product expansion is onset replicative senescence, state cell arrest characterized an increased release proinflammatory cytokines factors. little known about changes profile at different stages Some culture conditions bioprocessing techniques promise more effectively retaining anti-inflammatory MSC phenotype throughout Understanding how influence nature function MSCs, associated secretome, may provide key insights underlying mechanisms driving these alterations. Elucidating dynamic diverse each stage critical next step development standardized, safe, effective MSC-based therapies.

Language: Английский

---

Human umbilical cord-derived mesenchymal stromal cells improve myocardial fibrosis and restore miRNA-133a expression in diabetic cardiomyopathy

Stem Cell Research & Therapy, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 24, 2024

Diabetic cardiomyopathy (DCM) is a serious health-threatening complication of diabetes mellitus characterized by myocardial fibrosis and abnormal cardiac function. Human umbilical cord mesenchymal stromal cells (hUC-MSCs) are potential therapeutic tool for DCM via mechanisms such as the regulation microRNA (miRNA) expression inflammation. It remains unclear, however, whether hUC-MSC therapy has beneficial effects on function following different durations which mechanistic aspects modulated administration at stages its development. This study aimed to investigate intravenous hUC-MSCs hyperglycemia in an experimental male model determine candidate miRNAs, target mRNA inflammatory mediators.

Language: Английский

---

Fucoxanthin diminishes oxidative stress damage in human placenta-derived mesenchymal stem cells through the PI3K/Akt/Nrf-2 pathway

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Dec. 27, 2023

Abstract Placenta-derived mesenchymal stem cells (PL-MSCs) have therapeutic potential in various clinical contexts due to their regenerative and immunomodulatory properties. However, with increasing age or extensive vitro culture, viability function are gradually lost, thus restricting application. The primary cause of this deterioration is oxidative injury from free radicals. Therefore, enhancing cell restoring cellular repair mechanisms PL-MSCs an stress environment crucial context. Fucoxanthin, a carotenoid derived brown seaweed, demonstrates antioxidant activity by the production enzymes lowering levels reactive oxygen species (ROS). This study aimed determine whether fucoxanthin protects hydrogen peroxide (H 2 O )-induced stress. After characterization, were co-treated H for 24 h (co-treatment) pre-treated followed (pre-treatment). effects on proliferation examined using MTT assay. expression enzymes, PI3K/Akt/Nrf-2 intracellular ROS investigated fucoxanthin-treated compared untreated group. gene involvement specific pathways cytoprotective effect high-throughput NanoString nCounter analysis. results demonstrated that co-treatment pre-treatment restored proliferative capacity PL-MSCs. Fucoxanthin treatment increased cultured under conditions decreased accumulation. Markedly, could restore -treated High-throughput analysis revealed up-regulation genes involved survival pathways, including cycle proliferation, DNA damage down-regulation apoptosis autophagy pathways. rescues through pathway. Our data provide supporting evidence use as agent improve both vivo required increase effectiveness MSC expansion applications.

Language: Английский

---

Potency assays and biomarkers for cell-based advanced therapy medicinal products

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: June 9, 2023

Advanced Therapy Medicinal Products (ATMPs) based on somatic cells expanded

Language: Английский

---

Standard Radio-Iodine Labeling Protocols Impaired the Functional Integrity of Mesenchymal Stem/Stromal Cell Exosomes

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(7), P. 3742 - 3742

Published: March 27, 2024

Mesenchymal stem/stromal cells (MSCs) are an extensively studied cell type in clinical trials due to their easy availability, substantial ex vivo proliferative capacity, and therapeutic efficacy numerous pre-clinical animal models of disease. The prevailing understanding suggests that impact is mediated by the secretion exosomes. Notably, MSC exosomes present several advantages over MSCs as agents, non-living nature smaller size. However, despite promising potential, translation hindered incomplete biodistribution after administration. A primary obstacle this lies lack robust labels highly sensitive, capable directly easily tagging with minimal non-specific labeling artifacts, sensitive traceability background noise. One potential candidate address issue radioactive iodine. Protocols for iodinating tracking iodine live imaging well-established, application determining has been reported. Nevertheless, effects iodination on structural or functional activities have never thoroughly examined. In study, we investigate these report methods abrogate CD73 enzymatic activity Consequently, iodinated may reflect denatured rather than functionally intact ones.

Language: Английский

---

Molecular changes of cellular senescence in dental pulp stem cells during in vitro culture: a potential role of PSG4

Tissue and Cell, Journal Year: 2025, Volume and Issue: unknown, P. 102758 - 102758

Published: Jan. 1, 2025

Language: Английский

---

Senolytic elimination of senescent cells improved periodontal ligament stem cell-based bone regeneration partially through inhibiting YAP

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Journal Year: 2025, Volume and Issue: 1872(3), P. 119921 - 119921

Published: Feb. 18, 2025

Language: Английский

---