{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T22:54:11Z","timestamp":1787698451911,"version":"build-2784847793"},"reference-count":76,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T00:00:00Z","timestamp":1755129600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Bielefeld"},{"name":"Protestant Hospital of Bethel Foundation, University Hospital OWL of Bielefeld University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Natural killer (NK) cells are promising candidates for adoptive immunotherapy, but their clinical application requires standardized expansion protocols that yield functional cells in sufficient numbers. This study examined how initial seeding density and donor-intrinsic variability affect NK cell proliferation and receptor phenotype during in vitro expansion in a G-Rex\u00ae 24-well plate under IL-2 stimulation. NK cells from healthy donors were analyzed longitudinally by flow cytometry, and targeted SNP sequencing of selected receptor genes (IL2RA, IL2RB, FCGR3A, NCR1, KLRK1, and ICAM-1) was performed to assess potential genetic contributions. A seeding density of 2.0 \u00d7 106 cells\/cm2 promoted high expansion rates and favorable expression of activating receptors including CD16a, NKp46, and NKG2D. Nonetheless, marked inter-donor differences were observed. Some donors exhibited impaired proliferation and aberrant receptor expression, possibly associated with high-priority SNPs and distinct haplotype structures. Others showed robust proliferation despite the absence of identifiable genetic drivers, suggesting the involvement of variants in other genes or non-genetic mechanisms such as epigenetic priming or adaptive NK-cell differentiation. These results highlight the influence of both culture conditions and donor-intrinsic factors on NK-cell expansion outcomes. Integrating phenotypic and genetic analyses may improve the reproducibility and personalization of NK-cell-based manufacturing protocols for therapeutic use.<\/jats:p>","DOI":"10.3390\/cells14161252","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T14:51:46Z","timestamp":1755183106000},"page":"1252","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Donor Variability and Seeding Density Shape NK-Cell Proliferation and Surface Receptor Expression: Insights from an Integrated Phenotypic and Genetic Analysis"],"prefix":"10.3390","volume":"14","author":[{"given":"Neele","family":"Kusch","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Bielefeld University, 33615 Bielefeld, Germany"},{"name":"Forschungsverbund BioMedizin Bielefeld\/OWL FBMB e.V., 33617 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Storm","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Bielefeld University, 33615 Bielefeld, Germany"},{"name":"Forschungsverbund BioMedizin Bielefeld\/OWL FBMB e.V., 33617 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Macioszek","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Bielefeld University, 33615 Bielefeld, Germany"},{"name":"Department of Neurology, University Medical Center G\u00f6ttingen, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelius","family":"Knabbe","sequence":"additional","affiliation":[{"name":"Forschungsverbund BioMedizin Bielefeld\/OWL FBMB e.V., 33617 Bielefeld, Germany"},{"name":"Institute for Laboratory and Transfusion Medicine, Heart and Diabetes Centre NRW, Ruhr-University Bochum, 32545 Bad Oeynhausen, Germany"},{"name":"Medical Faculty Ostwestfalen-Lippe, University of Bielefeld, 33615 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Kaltschmidt","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Bielefeld University, 33615 Bielefeld, Germany"},{"name":"Forschungsverbund BioMedizin Bielefeld\/OWL FBMB e.V., 33617 Bielefeld, Germany"},{"name":"Department of Molecular Neurobiology, Bielefeld University, 33615 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Kaltschmidt","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Bielefeld University, 33615 Bielefeld, Germany"},{"name":"Forschungsverbund BioMedizin Bielefeld\/OWL FBMB e.V., 33617 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e20231222","DOI":"10.1084\/jem.20231222","article-title":"Five decades of natural killer cell discovery","volume":"221","author":"Lanier","year":"2024","journal-title":"J. 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