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Human Induced Multipotent Stem Cells: A Novel Alternative for Tissue-regeneration Strategies

Review of “Induction of muscle-regenerative multipotent stem cells from human adipocytes by PDGF-AB and 5-azacytidine” from Science Advances by Stuart P. Atkinson

A previous study from the laboratories of Vashe Chandrakanthan and John E. Pimanda (UNSW Sydney, Australia) reported how the treatment of terminally differentiated primary mouse osteocytes with the DNA hypomethylating agent azacytidine (AZA) [1, 2] and mitogen platelet-derived growth factor–AB (PDGF-AB) [3, 4] prompted their conversion into induced multipotent stem (iMS) cells [5]. Fascinatingly, iMS cells allowed for efficient in vivo tissue regeneration, suggesting their therapeutic implementation as an alternative to mesenchymal stem cells (MSCs). Additionally, further modifications to the derived protocol permitted the conversion of primary mouse and human adipocytes, a plentiful and easy to isolate cell source, into long-term repopulating iMS cells [5].

In their most recent study, Yeola et al. report on their improvements to the protocol for converting human adipocytes into iMS cells and describe the multilineage differentiation potential and in vivo regenerative capacity of the derived iMS cells [6]. Do human iMS cells now represent an exciting alternative to MSCs for enhanced tissue-regeneration strategies?

The authors first optimized both the concentrations of PDGF-AB and AZA and the treatment durations required to faithfully reprogram adipocytes isolated from adipose tissues from adult human donors aged between 27 and 66 years. Initial in vitro characterization of human iMS cells found that they resembled adipose-derived MSCs at the transcriptomic level, although iMS cells expressed higher levels of pluripotency-associated marker proteins. MSCs and iMS cells also displayed similar trilineage differentiation potential, although only iMS cells could generate pericyte-lined endothelial tubes in an extracellular matrix-based scaffold. Subsequent analyses of histone modification and DNA methylation profiles highlighted notable differences between iMS and MSCs at cis-regulatory regions of genes associated with cellular growth and systems development, which suggested to the authors that iMS cells may be able to respond to developmental cues for tissue development and differentiation in an enhanced manner when compared to MSCs.

The subsequent in vivo characterization of human iMS cells demonstrated that while they failed to form teratomas after implantation under the right kidney capsule of NSG mice, transplantation into a posterior-lateral intertransverse lumbar fusion mouse model [7] (a non-specific tissue injury xenograft model) provided evidence for long-term retention and a more significant contribution to bone, cartilage, muscle, and endothelium generation when compared to MSCs. Finally, the authors assessed the potential of human iMS cells to compete with resident murine muscle satellite cells and allow the tissue-specific/context-dependent regeneration of toxin-induced skeletal muscle injury [8]. Transplanted iMS cells again outperformed MSCs and permitted muscle-specific regeneration via the production of elevated numbers of human myofibers that displayed endogenous-like function without ectopic tissue formation.

Overall, the authors provide robust evidence for the implementation of iMS cells as an excellent alternative to MSCs in tissue-regeneration strategies. For more on this exciting advance, stay tuned to the Stem Cells Portal!

References

  1. Silverman LR, McKenzie DR, Peterson BL, et al., Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. Journal of Clinical Oncology 2006;24:3895-903.
  2. Dombret H, Seymour JF, Butrym A, et al., International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015;126:291-299.
  3. Heldin CH, Lennartsson J, and Westermark B, Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis. Journal of Internal Medicine 2018;283:16-44.
  4. Li F, Yu F, Xu X, et al., Evaluation of Recombinant Human FGF-2 and PDGF-BB in Periodontal Regeneration: A Systematic Review and Meta-Analysis. Scientific Reports 2017;7:65.
  5. Chandrakanthan V, Yeola A, Kwan JC, et al., PDGF-AB and 5-Azacytidine induce conversion of somatic cells into tissue-regenerative multipotent stem cells. Proceedings of the National Academy of Sciences 2016;113:E2306.
  6. Yeola A, Subramanian S, Oliver RA, et al., Induction of muscle-regenerative multipotent stem cells from human adipocytes by PDGF-AB and 5-azacytidine. Science Advances 2021;7:eabd1929.
  7. Rao RD, Bagaria VB, and Cooley BC, Posterolateral intertransverse lumbar fusion in a mouse model: surgical anatomy and operative technique. The Spine Journal 2007;7:61-67.
  8. Sacchetti B, Funari A, Remoli C, et al., No Identical “Mesenchymal Stem Cells” at Different Times and Sites: Human Committed Progenitors of Distinct Origin and Differentiation Potential Are Incorporated as Adventitial Cells in Microvessels. Stem Cell Reports 2016;6:897-913.