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An iPSC-based Cell Cotransplantation Therapy for Critical Limb Ischemia

Review of “Co-administration of Endothelial and Smooth Muscle Cells derived from Human Induced Pluripotent Stem Cells as a Therapy for Critical Limb Ischemia” from STEM CELLS Translational Medicine by Stuart P. Atkinson

Peripheral artery disease can progress from narrowed and hardened arteries to critical limb ischemia, whose onset associates with a high risk of limb amputation and cardiovascular death [1]. The endothelial cells and smooth muscle cells that form blood vessels represent key therapeutic cell types [2]; however, their isolation and cultivation represent important limitations to their widespread application. Endothelial cells [3] and smooth muscle cells [4] differentiated from pluripotent stem cell sources represent a possible solution, with an exciting study describing how induced pluripotent stem cell (iPSC)-derived endothelial cells and smooth muscle cells can cooperate to enhance neovascularization during dermal wound healing [5].

Now, researchers led by Jae Ho Kim (Pusan National University, Busan, South Korea) report on the therapeutic potential of an iPSC-derived endothelial cell and smooth muscle cell cotransplantation therapy for peripheral artery disease in a new STEM CELLS Translational Medicine study [6]. Fascinatingly, Park et al. describe how iPSC‐derived smooth muscle cells enhance the therapeutic efficacy of iPSC‐derived endothelial cells following cotransplantation in a murine hindlimb ischemia model via an exosome‐mediated paracrine mechanism.

The authors began by isolating CD34-expressing vascular progenitor cells from cultures of iPSCs induced to undergo mesodermal differentiation by exposure to the GSK3‐β inhibitor CHIR99021; subsequently, they employed distinct types of culture media to induce the differentiation of endothelial cells and smooth muscle cells [7]. Excitingly, the cotransplantation of the iPSC-derived endothelial cells and smooth muscle cells into a murine hindlimb ischemia model significantly improved blood perfusion and increased the limb salvage rate compared to the transplantation of either cell type alone. The authors linked these improvements to an increase in neovascularization in the ischemic limb, as they observed increased angiogenesis and the enhanced formation of capillaries and arteries/arterioles following cell cotransplantation.

In the final part of this exciting study, the authors moved in vitro to explore the mechanisms behind the improved therapeutic output of cell cotransplantation. Interestingly, both the conditioned medium from iPSC-derived smooth muscle cells and the exosomal fraction of the conditioned medium stimulated the migration, proliferation, and tubulation of endothelial cells to a similar degree, thereby providing evidence for an exosome‐mediated paracrine mechanism following cell cotransplantation in the murine hindlimb ischemia model.

This exciting study provides evidence for the use of iPSC-derived progenitors as an alternative to those isolated from bone marrow or peripheral blood, which generally display high variability regarding their therapeutic efficacy, for the production of the vast amounts of endothelial and smooth muscle cells needed for therapeutic purposes. Given these encouraging findings, the authors next hope to identify the pro-regenerative factors present in smooth muscle cell-derived exosomes and develop means to produce iPSC-derived endothelial cells and smooth muscle cells at a larger scale and efficiently isolate exosomes.

For more on stem cell transplantation therapies for the treatment of peripheral artery disease, stay tuned to the Stem Cells Portal!


  1. Frangogiannis NG, Cell therapy for peripheral artery disease. Current Opinion in Pharmacology 2018;39:27-34.
  2. Foubert P, Matrone G, Souttou B, et al., Coadministration of Endothelial and Smooth Muscle Progenitor Cells Enhances the Efficiency of Proangiogenic Cell-Based Therapy. Circulation Research 2008;103:751-760.
  3. Park S-J, Moon S-H, Lee H-J, et al., A comparison of human cord blood- and embryonic stem cell-derived endothelial progenitor cells in the treatment of chronic wounds. Biomaterials 2013;34:995-1003.
  4. Cheung C and Sinha S, Human embryonic stem cell-derived vascular smooth muscle cells in therapeutic neovascularisation. Journal of Molecular and Cellular Cardiology 2011;51:651-664.
  5. Kim KL, Song S-H, Choi K-S, et al., Cooperation of Endothelial and Smooth Muscle Cells Derived from Human Induced Pluripotent Stem Cells Enhances Neovascularization in Dermal Wounds. Tissue Engineering Part A 2013;19:2478-2485.