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Enhanced hMSC-based Therapies via Metabolic Rewiring?

Review of “Metabolic Reconfiguration Supports Reacquisition of Primitive Phenotype in Human Mesenchymal Stem Cell Aggregates” from Stem Cells by Stuart P. Atkinson

Good things always seem to happen when you surround yourself with like-minded friends, and things are no different for human mesenchymal stem cells (hMSCs)! hMSCs aggregates formed in non-adherent culture display enhanced stem cell properties, and hence regenerative potential, when compared to hMSCs grown in adherent culture [1]. While many studies suggest that aggregation mimics the in vivo hMSCs microenvironment [1, 2] the exact molecular mechanisms behind aggregation-mediated enhancements in stem cell properties remain unclear.

Now, in a new Stem Cells study, researchers from the laboratory of Teng Ma (Florida State University, USA) now demonstrate that metabolic “rewiring” leads to the enhancement of stem cell characteristics observed in aggregated hMSCs [3]. Can we use this information to improve conventional hMSC culture and create enhanced hMSC-based therapies?

Growing hMSCs in a 3D aggregate culture generated cells exhibiting a more primitive phenotype which included smaller cell size, spindle cell shape, increased pluripotency marker expression, increased colony forming ability, lower senescence, higher migratory capacity, and increased levels of autophagy, a process which helps to eliminate damaged proteins and organelles and maintain hMSC viability.

However, aggregated hMSCs also displayed significant mitochondrial alterations including morphological changes, reduced mitochondrial membrane potential and, importantly, the previously mentioned metabolic rewiring. This manifested in aggregated hMSCs as a switch from exploiting oxidative phosphorylation (OXPHOS) to glycolysis, a metabolic pathway utilized by pluripotent stem cells to generate energy.

But does a link exist between stemness and metabolic rewiring? Interestingly, reactivation of OXPHOS in aggregated hMSCs attenuated the upregulation of pluripotency-associated gene expression, while OXPHOS inactivation in adherent hMSCs promoted the expression of pluripotency- and autophagy-associated genes and permitted metabolic reconfiguration towards glycolysis.

hMSCs represent an important and widely used cell type in therapeutic interventions, although current adherent culture techniques appear to exhaust this potential over time. But do we now have a remedy for this problem? This study of hMSC aggregation suggests that small molecule-directed metabolic rewiring could promote stemness in adherent cells and lead to enhanced hMSC-based therapies.

Stay tuned to the Stem Cells Portal to hear about continuing studies which will identify promising candidate small molecules, assess their effects, and evaluate the functional consequences of metabolic rewiring in hMSC-based therapies.

Discussion Points

  • Will metabolic rewiring lead to enhanced in vivo function of transplanted hMSCs?
  • What signaling pathways mediate aggregation-induced changes?
  • Can other stem cell types take advantage of 3D growth conditions?


  1. Follin B, Juhl M, Cohen S, et al. Increased Paracrine Immunomodulatory Potential of Mesenchymal Stromal Cells in Three-Dimensional Culture. Tissue Eng Part B Rev 2016;22:322-329.
  2. Pennock R, Bray E, Pryor P, et al. Human cell dedifferentiation in mesenchymal condensates through controlled autophagy. Sci Rep 2015;5:13113.
  3. Liu Y, Munoz N, Tsai AC, et al. Metabolic Reconfiguration Supports Reacquisition of Primitive Phenotype in Human Mesenchymal Stem Cell Aggregates. Stem Cells 2017;35:398-410.