Strategies toward virus and prion safe human platelet lysates

Blümel, Johannes; Schwantes, Astrid; Baylis, Sally A.; Stühler, Albert

doi:10.1111/trf.15581

Cited by 10 publications

(22 citation statements)

References 5 publications

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“…Despite the growing use of hPL in vitro cell culture and the urgent interest in translational purposes, the application of hPL needs to be defined properly on quality issues and safety criteria (e.g., open questions such as virus inactivation or prion transmission) [16,17]. These steps are essential, focusing on the differences between the manufacturing and clinical implications of hPL and the traditional fields of transfusion medicine.…”

Section: Introductionmentioning

confidence: 99%

Human platelet lysate as a potential clinical-translatable supplement to support the neurotrophic properties of human adipose-derived stem cells

et al. 2020

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Background The autologous nerve graft, despite its donor site morbidity and unpredictable functional recovery, continues to be the gold standard in peripheral nerve repair. Rodent research studies have shown promising results with cell transplantation of human adipose-derived stem cells (hADSC) in a bioengineered conduit, as an alternative strategy for nerve regeneration. To achieve meaningful clinical translation, cell therapy must comply with biosafety. Cell extraction and expansion methods that use animal-derived products, including enzymatic adipose tissue dissociation and the use of fetal bovine serum (FBS) as a culture medium supplement, have the potential for transmission of zoonotic infectious and immunogenicity. Human-platelet-lysate (hPL) serum has been used in recent years in human cell expansion, showing reliability in clinical applications. Methods We investigated whether hADSC can be routinely isolated and cultured in a completely xenogeneic-free way (using hPL culture medium supplement and avoiding collagenase digestion) without altering their physiology and stem properties. Outcomes in terms of stem marker expression (CD105, CD90, CD73) and the osteocyte/adipocyte differentiation capacity were compared with classical collagenase digestion and FBS-supplemented hADSC expansion. Results We found no significant differences between the two examined extraction and culture protocols in terms of cluster differentiation (CD) marker expression and stem cell plasticity, while hADSC in hPL showed a significantly higher proliferation rate when compared with the usual FBS-added medium. Considering the important key growth factors (particularly brain-derived growth factor (BDNF)) present in hPL, we investigated a possible neurogenic commitment of hADSC when cultured with hPL. Interestingly, hADSC cultured in hPL showed a statistically higher secretion of neurotrophic factors BDNF, glial cell-derived growth factor (GDNF), and nerve-derived growth factor (NFG) than FBS-cultured cells. When cocultured in the presence of primary neurons, hADSC which had been grown under hPL supplementation, showed significantly enhanced neurotrophic properties. Conclusions The hPL-supplement medium could improve cell proliferation and neurotropism while maintaining stable cell properties, showing effectiveness in clinical translation and significant potential in peripheral nerve research.

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Section: Introductionmentioning

confidence: 99%

Human platelet lysate as a potential clinical-translatable supplement to support the neurotrophic properties of human adipose-derived stem cells

et al. 2020

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“…The possibility of using platelet lysate supplements in place of FBS provides a valuable xeno-free option for propagating human cells used for cell therapy procedures [2À5,10]. Pooling of a minimum number of allogeneic PC donations, needed to ensure platelet lysate consistency in quality and performance [5,27,28], increases viral risks [5,19,29]. Lysates can now be prepared from PC donations that have been pathogen-reduced by psoralen/UVA [30,31] or UV [32] treatments, without detrimentally affecting the MSC expansion capacity compared with FBS, thereby providing an important step forward in virus safety.…”

Section: Discussionmentioning

confidence: 99%

“…Lysates can now be prepared from PC donations that have been pathogen-reduced by psoralen/UVA [30,31] or UV [32] treatments, without detrimentally affecting the MSC expansion capacity compared with FBS, thereby providing an important step forward in virus safety. Application of pathogen reduction by psoralen/UVA treatment after platelet lysis [33], and gamma-irradiation of pooled HPL [19) may also be alternative feasible approaches recently evaluated. However, all pathogen-reduction technologies have limits in their capacities, and pooling increases the risk of contamination by (i) window period donations, (ii) viruses that are not tested for, (iii) emerging infectious agents and (iv) potentially prions [13À17,19].…”

Section: Discussionmentioning

confidence: 99%

“…However, all pathogen-reduction technologies have limits in their capacities, and pooling increases the risk of contamination by (i) window period donations, (ii) viruses that are not tested for, (iii) emerging infectious agents and (iv) potentially prions [13À17,19]. These reasons make the implementation of "orthogonal" pathogenreduction treatments of platelet lysates, as done for a long time in the plasma fractionation industry [34,35], highly desirable as stressed in recent publications [5,19,29]. We recently showed the feasibility of preparing platelet lysates subjected to psoralen/UVA and solvent/ detergent [22], a treatment that is highly efficient against lipid-enveloped viruses [34À36].…”

Section: Discussionmentioning

confidence: 99%

“…Particular concerns exist with regard to untested emerging viruses, such as West Nile virus, Dengue virus, Zika virus, or coronaviruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV)-1 or -2 if they are present in an infectious form in the blood of asymptomatic donors [13À17]. The ultimate approach to ensure the pathogen safety of pooled lysates, as for any pooled blood products, is by implementing one or two robust and complementary pathogen inactivation or removal treatments [18,19]. Among those, one robust pathogen removal technology is nanofiltration, a step of filtration using membranes of a few nanometers capable of removing viruses, and possibly other pathogens like prions, based on size-exclusion [20,21].…”

Section: Introductionmentioning

confidence: 99%

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Nanofiltration of growth media supplemented with human platelet lysates for pathogen-safe xeno-free expansion of mesenchymal stromal cells

et al. 2020

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Background aims: Human platelet lysate can replace fetal bovine serum (FBS) for xeno-free ex vivo expansion of mesenchymal stromal cells (MSCs), but pooling of platelet concentrates (PCs) increases risks of pathogen transmission. We evaluated the feasibility of performing nanofiltration of platelet lysates and determined the impact on expansion of bone marrowÀderived MSCs. Methods: Platelet lysates were prepared by freeze-thawing of pathogen-reduced (Intercept) PCs suspended in 65% storage solution (SPP+) and 35% plasma, and by serum-conversion of PCs suspended in 100% plasma. Lysates were added to the MSC growth media at 10% (v/v), filtered and subjected to cascade nanofiltration on 35-and 19-nm Planova filters. Media supplemented with 10% starting platelet lysates or FBS were used as the controls. Impacts of nanofiltration on the growth media composition, removal of platelet extracellular vesicles (PEVs) and MSC expansion were evaluated. Results: Nanofiltration did not detrimentally affect contents of total protein and growth factors or the biochemical composition. The clearance factor of PEVs was >3 log values. Expansion, proliferation, membrane markers, differentiation potential and immunosuppressive properties of cells in nanofiltered media were consistently better than those expanded in FBS-supplemented media. Compared with FBS, chondrogenesis and osteogenesis genes were expressed more in nanofiltered media, and there were fewer senescent cells over six passages. Conclusions: Nanofiltration of growth media supplemented with two types of platelet lysates, including one prepared from pathogen-reduced PCs, is technically feasible. These data support the possibility of developing pathogen-reduced xeno-free growth media for clinical-grade propagation of human cells.

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Neuroprotective activity of a virus‐safe nanofiltered human platelet lysate depleted of extracellular vesicles in Parkinson's disease and traumatic brain injury models

Delila

Nebie

et al. 2022

Bioengineering & Transla Med

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Brain administration of human platelet lysates (HPL) is a potential emerging biotherapy of neurodegenerative and traumatic diseases of the central nervous system. HPLs being prepared from pooled platelet concentrates, thereby increasing viral risks, manufacturing processes should incorporate robust virus‐reduction treatments. We evaluated a 19 ± 2‐nm virus removal nanofiltration process using hydrophilic regenerated cellulose hollow fibers on the properties of a neuroprotective heat‐treated HPL (HPPL). Spiking experiments demonstrated >5.30 log removal of 20–22‐nm non‐enveloped minute virus of mice‐mock particles using an immuno‐quantitative polymerase chain reaction assay. The nanofiltered HPPL (NHPPL) contained a range of neurotrophic factors like HPPL. There was >2 log removal of extracellular vesicles (EVs), associated with decreased expression of pro‐thrombogenic phosphatidylserine and procoagulant activity. LC‐MS/MS proteomics showed that ca. 80% of HPPL proteins, including neurotrophins, cytokines, and antioxidants, were still found in NHPPL, whereas proteins associated with some infections and cancer‐associated pathways, pro‐coagulation and EVs, were removed. NHPPL maintained intact neuroprotective activity in Lund human mesencephalic dopaminergic neuron model of Parkinson's disease (PD), stimulated the differentiation of SH‐SY5Y neuronal cells and showed preserved anti‐inflammatory function upon intranasal administration in a mouse model of traumatic brain injury (TBI). Therefore, nanofiltration of HPL is feasible, lowers the viral, prothrombotic and procoagulant risks, and preserves the neuroprotective and anti‐inflammatory properties in neuronal pre‐clinical models of PD and TBI.

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Strategies toward virus and prion safe human platelet lysates

Cited by 10 publications

References 5 publications

Human platelet lysate as a potential clinical-translatable supplement to support the neurotrophic properties of human adipose-derived stem cells

Human platelet lysate as a potential clinical-translatable supplement to support the neurotrophic properties of human adipose-derived stem cells

Nanofiltration of growth media supplemented with human platelet lysates for pathogen-safe xeno-free expansion of mesenchymal stromal cells

Neuroprotective activity of a virus‐safe nanofiltered human platelet lysate depleted of extracellular vesicles in Parkinson's disease and traumatic brain injury models

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