Mitochondrial donation recapitulates physiological niche signalling to promote metabolic plasticity, expansion, and engraftment of hematopoietic progenitors

Mitochondrial donation recapitulates physiological niche signalling to promote metabolic plasticity, expansion, and engraftment of hematopoietic progenitors | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Mitochondrial donation recapitulates physiological niche signalling to promote metabolic plasticity, expansion, and engraftment of hematopoietic progenitors Maroun Khoury, Radmila Velarde, Angela Court, Gino Nardocci, André Weber, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8844855/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Umbilical cord blood (UCB) transplantation effectively treats pediatric hematologic disorders, but insufficient multipotent progenitors delay immune reconstitution, severely restricting its clinical application in adults. Here, we established that mesenchymal stromal cells’ mitochondrial donation to UCB hematopoietic stem cells accelerates immune recovery, identifying mitochondrial donation as a constitutive physiological regulator. Using Prx1CreER-driven mitochondrial reporters, we demonstrate that stromal niche cells spontaneously transfer mitochondria to hematopoietic progenitors in vivo. Mechanistically, this transfer reinforces glycolytic quiescence in stem cells while activating oxidative phosphorylation in multipotent progenitors. This compartment-specific remodelling drives >100-fold multipotent progenitor enrichment and 40-fold early progenitor expansion. Crucially, the respiratory competence of transferred mitochondria is essential, since respiration-deficient mitochondria fail to support this reprogramming. In competitive xenografts, mitochondrial-enhanced UCB achieves 3-fold greater engraftment and accelerated T-cell reconstitution. These findings reveal that mitochondrial integrity orchestrates metabolic programs to balance stem cell preservation with therapeutic amplification, offering a strategy to optimize UCB transplantation. Biological sciences/Stem cells/Haematopoietic stem cells Biological sciences/Stem cells/Mesenchymal stem cells Full Text Additional Declarations Yes there is potential Competing Interest. M.K. is a university professor and receives stipends from Cells for Cells, through a contract research with the university of los Andes, Chile; others declare no conflicts Scientific Ethics Committee of Universidad de los Andes approved the study Supplementary Files SuppFigureswlegendsVelardeetalV3.pdf Supplementary Figures S1 to S10 Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8844855","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":613507838,"identity":"b81c0640-b4c6-4e8f-a954-8ed44578d881","order_by":0,"name":"Maroun 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