You are here

| ESCs/iPSCs

TGFβ Inhibition – The Key to Endothelial Cell-based Therapeutics?

Comment

Discuss

Review of “Suppression of Transforming Growth Factor-β Signaling Delays Cellular Senescence and Preserves the Function of Endothelial Cells Derived from Human Pluripotent Stem Cells” from Stem Cells Translational Medicine by Stuart P. Atkinson

The differentiation of human pluripotent stem cells (hPSCs) into endothelial cells represents an exciting means to produce the vast amounts of cells required for tissue engineering purposes and the treatment of cardiovascular diseases. Researchers from the lab of Zack Z. Wang (Johns Hopkins University, Baltimore, USA) previously demonstrated that human embryonic stem cell-derived endothelial cells (hESCs-ECs) formed functional blood vessels in a mouse model [1], although their limited expansion potential and early senescence still represent important obstacles to widespread application [2].

In their new study, published in Stem Cells Translational Medicine, the team explored endothelial senescence in cells derived from both hESCs and human induced pluripotent stem cells (hiPSCs) and propose a new means to maintain functional ECs in long-term culture: the inhibition of transforming growth factor β1 (TGFβ1) signaling [3].

The study first confirmed that hPSC-derived ECs had a limited cell expansion capacity, as ECs stopped growing after only a few passages in vitro. This growth inhibition correlated with a loss in functionality, as evidenced by reduced vascular formation capacity in vitro and in vivo, a reduction in factors that controls EC proliferation and migration, and an increase in EC senescence.

Overall, this does not bode well for EC-based therapeutics, and so the authors screened for compounds that could maintain EC growth capacity and functionality in the long term. Their screening process soon identified SB431542 and A83-01 as compounds of interest, with both specifically blocking the activity of TGFβ type I receptors. TGFβ1-inhibition in EC cultures permitted a reduction in senescent EC number and an increase in long-term EC growth capacity and functionality. Encouragingly, TGFβ1-inhibitor treated ECs also demonstrated improbed in vivo functionality as demonstrated by high levels of revascularization after transplantation in a hind-limb ischemia mouse model (See Figure).

This exciting new study suggests that TGFβ inhibition may be the key to endothelial cell-based therapeutics allowing long-term culture and expansion to cell number levels relevant for clinical applications. Furthermore, this data also provides an insight into the molecular mechanisms behind vascular aging and highlights TGFβ inhibition as a means to target endothelial cells in vivo as well as in vitro.

References

  1. Wang ZZ, Au P, Chen T, et al. Endothelial cells derived from human embryonic stem cells form durable blood vessels in vivo. Nat Biotechnol 2007;25:317-318.
  2. Feng Q, Lu SJ, Klimanskaya I, et al. Hemangioblastic derivatives from human induced pluripotent stem cells exhibit limited expansion and early senescence. Stem Cells 2010;28:704-712.
  3. Bai H, Gao Y, Hoyle DL, et al. Suppression of Transforming Growth Factor-β Signaling Delays Cellular Senescence and Preserves the Function of Endothelial Cells Derived from Human Pluripotent Stem Cells. STEM CELLS Translational Medicine 2017;6:589-600.