Hypothermia and nutrient deprivation alter viability of human adipose-derived mesenchymal stem cells

Kubrova, Eva; Qu, Wenchun; Galvan, M. Lizeth; Paradise, Christopher R.; Yang, Juan; Dietz, Allan B.; Dudakovic, Amel; Smith, Jay; Wijnen, André J. van

doi:10.1016/j.gene.2019.144058

Cited by 9 publications

(11 citation statements)

References 41 publications

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“…Therefore, the remarkable increase in FGF-2 secretion was probably connected with processes that occurred during storage. It is known that the prolonged storage of cells and tissues below physiological temperatures results in the moderation of metabolic activity and cell cycle deceleration or the initiation of apoptotic processes [47]. In this study, the significant upregulation of P21 was detected after 2 and 6 days of storage, indicating the possible temperature-induced cell cycle arrest.…”

Section: Discussionmentioning

confidence: 48%

Hypothermic Storage of 3D Cultured Multipotent Mesenchymal Stromal Cells for Regenerative Medicine Applications

et al. 2022

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The regulatory requirements in cell processing, in the choice of a biomaterial scaffold and in quality control analysis, have to be followed in the clinical application of tissue-engineered grafts. Confirmation of sterility during quality control studies requires prolonged storage of the cell-based construct. After storage, preservation of the functional properties of the cells is an important prerequisite if the cells are to be used for cell-based tissue therapies. The study presented here shows the generation of 3D constructs based on Wharton’s jelly multipotent mesenchymal stromal cells (WJ-MSCs) and the clinically-acceptable HyaloFast® scaffold, and the effect of two- and six-day hypothermic storage of 3D cell-based constructs on the functional properties of populated cells. To study the viability, growth, gene expression, and paracrine secretion of WJ-MSCs within the scaffolds before and after storage, xeno-free culture conditions, metabolic, qPCR, and multiplex assays were applied. The WJ-MSCs adhered and proliferated within the 3D HyaloFast®. Our results show different viability of the cells after the 3D constructs have been stored under mild (25 °C) or strong (4 °C) hypothermia. At 4 °C, the significant decrease of metabolic activity of WJ-MSCs was detected after 2 days of storage, with almost complete cell loss after 6 days. In mild hypothermia (25 °C) the decrease in metabolic activity was less remarkable, confirming the suitability of these conditions for cell preservation in 3D environment. The significant changes were detected in gene expression and in the paracrine secretion profile after 2 and 6 days of storage at 25 °C. The results presented in this study are important for the rapid transfer of tissue engineering approaches into clinical applications.

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Section: Discussionmentioning

confidence: 48%

Hypothermic Storage of 3D Cultured Multipotent Mesenchymal Stromal Cells for Regenerative Medicine Applications

et al. 2022

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“…MSCs are fundamentally responsive to subtle changes in their environment. MSCs respond to changes in atmospheric gases ( Lin et al, 2014 ; Gorgun et al, 2021 ; Roemeling-Van Rhijn et al, 2013 ; Ejtehadifar et al, 2015 ; Kang et al, 2019 ; von Bahr et al, 2019 ), temperature ( Stolzing et al, 2006 ; Kubrova et al, 2020 ; Shimoni et al, 2020 ), hydrostatic pressure ( Steward et al, 2012 ; Becquart et al, 2016 ; Pattappa et al, 2019 ) and aggregation ( Robb et al, 2019 ; Yuan et al, 2019 ; Burand et al, 2020 ; Xie et al, 2021 ). It is surprising then, that the steps and duration between dose preparation and delivery of MSC therapies are ill-defined and under-reported.…”

Section: Discussionmentioning

confidence: 99%

From Vial to Vein: Crucial Gaps in Mesenchymal Stromal Cell Clinical Trial Reporting

Wiese

Wood

Braid

2022

Front. Cell Dev. Biol.

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Retrospective analysis of clinical trial outcomes is a vital exercise to facilitate efficient translation of cellular therapies. These analyses are particularly important for mesenchymal stem/stromal cell (MSC) products. The exquisite responsiveness of MSCs, which makes them attractive candidates for immunotherapies, is a double-edged sword; MSC clinical trials result in inconsistent outcomes that may correlate with underlying patient biology or procedural differences at trial sites. Here we review 45 North American MSC clinical trial results published between 2015 and 2021 to assess whether these reports provide sufficient information for retrospective analysis. Trial reports routinely specify the MSC tissue source, autologous or allogeneic origin and administration route. However, most methodological aspects related to cell preparation and handling immediately prior to administration are under-reported. Clinical trial reports inconsistently provide information about cryopreservation media composition, delivery vehicle, post-thaw time and storage until administration, duration of infusion, and pre-administration viability or potency assessments. In addition, there appears to be significant variability in how cell products are formulated, handled or assessed between trials. The apparent gaps in reporting, combined with high process variability, are not sufficient for retrospective analyses that could potentially identify optimal cell preparation and handling protocols that correlate with successful intra- and inter-trial outcomes. The substantial preclinical data demonstrating that cell handling affects MSC potency highlights the need for more comprehensive clinical trial reporting of MSC conditions from expansion through delivery to support development of globally standardized protocols to efficiently advance MSCs as commercial products.

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“…We hypothesized three possible causes of poor cell-delivery efficiency during intravenous infusion: (1) acute cell death due to nutrient deprivation and hypoxic stress in the suspension solution or biomechanical stress during infusion; (2) cell adhesion to the walls of the apparatus, such as the infusion bag, syringe, or infusion tube; and (3) cell aggregation during storage and infusion. Temperature, solution type, and cell density of the cell preparation, as well as storage, can affect the metabolic activity of MSC, thus altering their viability and function [ 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. It has been reported that the viability of hADSC in NS is better maintained at lower temperatures (4 °C) than at room temperature (37 °C) [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that the viability of hADSC in NS is better maintained at lower temperatures (4 °C) than at room temperature (37 °C) [ 42 , 43 ]. On the other hand, Kubrova et al compared the viabilities of hADSC suspended in lactate Ringer’s solution and stored at physiological temperature (37 °C), room temperature (23 °C), or low temperature (4 °C) for 4 h, and reported that room temperature was optimal [ 44 ]. Because the current study focused on cell delivery in infused ADSC immediately after preparation, we considered the effect of temperature-related acute cell death to be minimal due to their short storage time, and we therefore prepared the cADSC at room temperature in this study.…”

Section: Discussionmentioning

confidence: 99%

Optimal Intravenous Administration Procedure for Efficient Delivery of Canine Adipose-Derived Mesenchymal Stem Cells

Yasumura

Teshima

Taira

et al. 2022

IJMS

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Mesenchymal stem cells (MSC) are currently being investigated for their therapeutic applications in a wide range of diseases. Although many studies examined peripheral venous administration of MSC, few have investigated the detailed intravenous administration procedures of MSC from their preparation until they enter the body. The current study therefore aimed to explore the most efficient infusion procedure for MSC delivery by preparing and infusing them under various conditions. Canine adipose-derived mesenchymal stem cells (cADSC) were infused using different infusion apparatuses, suspension solutions, allogenic serum supplementation, infusion time and rates, and cell densities, respectively. Live and dead cell counts were then assessed by manual measurements and flow cytometry. Efficiency of live- and dead-cell infusion and cell viability were calculated from the measured cell counts and compared under each condition. Efficiency of live-cell infusion differed significantly according to the infusion apparatus, infusion rate, and combination of cell density and serum supplementation. Cell viability after infusion differed significantly between the infusion apparatuses. The optimal infusion procedure resulting in the highest cell delivery and viability involved suspending cADSC in normal saline supplemented with 5% allogenic serum at a density of 5 × 105 cells/mL, and infusing them using an automatic infusion device for 15 min. This procedure is therefore recommended as the standard procedure for the intravenous administration of ADSC in terms of cell-delivery efficiency.

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Hypothermia and nutrient deprivation alter viability of human adipose-derived mesenchymal stem cells

Cited by 9 publications

References 41 publications

Hypothermic Storage of 3D Cultured Multipotent Mesenchymal Stromal Cells for Regenerative Medicine Applications

Hypothermic Storage of 3D Cultured Multipotent Mesenchymal Stromal Cells for Regenerative Medicine Applications

From Vial to Vein: Crucial Gaps in Mesenchymal Stromal Cell Clinical Trial Reporting

Optimal Intravenous Administration Procedure for Efficient Delivery of Canine Adipose-Derived Mesenchymal Stem Cells

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