{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:01:35Z","timestamp":1792789295468,"version":"4.5.0"},"reference-count":80,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and High Education of the Republic of Kazakhstan","award":["AP26103353"],"award-info":[{"award-number":["AP26103353"]}],"id":[{"id":"https:\/\/ror.org\/05tyne317","id-type":"ROR","asserted-by":"crossref"}]},{"award":["AP26103353"],"award-info":[{"award-number":["AP26103353"]}],"id":[{"id":"https:\/\/ror.org\/05tyne317","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Osteonecrosis of the femoral head (ONFH) is a progressive ischemic bone disorder that may lead to subchondral fracture, femoral-head collapse, and total hip arthroplasty. Impaired regeneration reflects persistent ischemia, endothelial dysfunction, defective angiogenesis and bone remodeling, inflammation, oxidative stress, and dysfunction of endogenous mesenchymal stromal cells (MSCs). Although MSC therapy, particularly with core decompression in precollapse ONFH, is a promising joint-preserving approach, conventional two-dimensional (2D)-expanded MSCs are limited by poor survival and retention, anoikis, disrupted cell\u2013cell and cell\u2013extracellular matrix interactions, and loss of potency during ex vivo expansion. Three-dimensional MSC spheroids may overcome several of these limitations by preserving intercellular and matrix interactions and enhancing resistance to ischemic stress, paracrine signaling, angiogenic activity, immunomodulation, and osteogenic competence. Hypoxia-responsive signaling, autophagy, trophic-factor secretion, and extracellular vesicle-mediated communication may promote angiogenesis\u2013osteogenesis coupling and the restoration of the ischemic bone\u2013vascular niche. This review summarizes the pathophysiological barriers to ONFH regeneration, current evidence and limitations of conventional MSC therapy, biological mechanisms underlying MSC-spheroid activity, and emerging strategies for therapeutic optimization. Importantly, direct evidence demonstrating the superiority of MSC spheroids over conventional MSC preparations specifically in ONFH remains limited. Future translation will require disease-specific comparative studies, standardized GMP-compatible manufacturing, validated potency assays and clinically practical delivery systems.<\/jats:p>","DOI":"10.3390\/cells15191787","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T15:20:59Z","timestamp":1790781659000},"page":"1787","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mesenchymal Stromal Cell Spheroids as an Emerging Regenerative Strategy for Osteonecrosis of the Femoral Head"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0528-1430","authenticated-orcid":false,"given":"Sholpan","family":"Mukhlis","sequence":"first","affiliation":[{"name":"Stem Cell Laboratory, National Center for Biotechnology, 010000 Astana, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meruyert","family":"Imanbekova","sequence":"additional","affiliation":[{"name":"Stem Cell Laboratory, National Center for Biotechnology, 010000 Astana, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina","family":"Saginova","sequence":"additional","affiliation":[{"name":"National Scientific Center for Traumatology and Orthopedics After Academician N.D. Batpenov, 010000 Astana, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madina","family":"Sarsenova","sequence":"additional","affiliation":[{"name":"Stem Cell Laboratory, National Center for Biotechnology, 010000 Astana, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aida","family":"Nurgaliyeva","sequence":"additional","affiliation":[{"name":"Stem Cell Laboratory, National Center for Biotechnology, 010000 Astana, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nursulu","family":"Altaeva","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Molecular Biology, Astana Medical University, 010000 Astana, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5029-5255","authenticated-orcid":false,"given":"Vyacheslav","family":"Ogay","sequence":"additional","affiliation":[{"name":"Stem Cell Laboratory, National Center for Biotechnology, 010000 Astana, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e177","DOI":"10.3346\/jkms.2021.36.e177","article-title":"Osteonecrosis of the femoral head: An updated review of ARCO on pathogenesis, staging and treatment","volume":"36","author":"Hines","year":"2021","journal-title":"J. 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