Adipose-derived dual cell therapy enhances arteriogenesis and limb preservation through vascular integration in critical limb ischemia

1. Golledge, J. Update on the pathophysiology and medical treatment of peripheral artery disease. Nat. Rev. Cardiol. 19, 456–474 (2022).

   Google Scholar 

2. Qadura, M., Terenzi, D. C., Verma, S., Al-Omran, M. & Hess, D. A. Concise review: cell therapy for critical limb ischemia: an integrated review of preclinical and clinical studies. Stem Cells 36, 161–171 (2018).

   Google Scholar 

3. Jansen-Chaparro, S. et al. Statins and peripheral arterial disease: a narrative review. Front. Cardiovasc. Med. 8, 777016 (2021).

   Google Scholar 

4. Dormandy, J. A. & Rutherford, R. B. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Consensus (TASC). J. Vasc. Surg. 31, S1–296 (2000).

   Google Scholar 

5. Gupta, R. & Losordo, D. W. Cell therapy for critical limb ischemia: moving forward one step at a time. Circ. Cardiovasc. Interv. 4, 2–5 (2011).

   Google Scholar 

6. Shirbaghaee, Z., Hassani, M., Heidari Keshel, S. & Soleimani, M. Emerging roles of mesenchymal stem cell therapy in patients with critical limb ischemia. Stem Cell Res. Ther. 13, 462 (2022).

   Google Scholar 

7. Park, G. et al. Identification of CD141+vasculogenic precursor cells from human bone marrow and their endothelial engagement in the arteriogenesis by co-transplantation with mesenchymal stem cells. Stem Cell Res. Ther. 15, 388 (2024).

   Google Scholar 

8. Kolf, C. M., Cho, E. & Tuan, R. S. Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation. Arthritis Res. Ther. 9, 204 (2007).

   Google Scholar 

9. Lozano Navarro, L. V. et al. Mesenchymal stem cells for critical limb ischemia: their function, mechanism, and therapeutic potential. Stem Cell Res. Ther. 13, 345 (2022).

   Google Scholar 

10. Bagno, L., Hatzistergos, K. E., Balkan, W. & Hare, J. M. Mesenchymal stem cell-based therapy for cardiovascular disease: Progress and challenges. Mol. Ther. 26, 1610–1623 (2018).

    Google Scholar 

11. Guo, Y., Peng, Y., Zeng, H. & Chen, G. Progress in mesenchymal stem cell therapy for ischemic stroke. Stem Cells Int. 2021, 9923566 (2021).

    Google Scholar 

12. Yang, Q. et al. Combined transplantation of adipose tissue-derived stem cells and endothelial progenitor cells improve diabetic erectile dysfunction in a rat model. Stem Cells Int. 2020, 2154053 (2020).

    Google Scholar 

13. Kim, D. Y. et al. Platelet-derived growth factor-BB priming enhances vasculogenic capacity of bone marrow-derived endothelial precursor like cells. Tissue Eng. Regen. Med. 20, 695–704 (2023).

    Google Scholar 

14. Alev, C., Ii, M. & Asahara, T. Endothelial progenitor cells: a novel tool for the therapy of ischemic diseases. Antioxid. Redox Signal. 15, 949–965 (2011).

    Google Scholar 

15. MacAskill, M. G. et al. Robust revascularization in models of limb ischemia using a clinically translatable human stem cell-derived endothelial cell product. Mol. Ther. 26, 1669–1684 (2018).

    Google Scholar 

16. Cheng, F. et al. Conversion of human adipose-derived stem cells into functional and expandable endothelial-like cells for cell-based therapies. Stem Cell Res. Ther. 9, 350 (2018).

    Google Scholar 

17. Minamino, K. et al. Macrophage colony-stimulating factor (M-CSF), as well as granulocyte colony-stimulating factor (G-CSF), accelerates neovascularization. Stem Cells 23, 347–354 (2005).

    Google Scholar 

18. Popescu, S. et al. Dual stem cell therapy improves the myocardial recovery post-infarction through reciprocal modulation of cell functions. Int. J. Mol. Sci. 22, 5631 (2021).

    Google Scholar 

19. Kuo, T. K. et al. Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells. Gastroenterology 134, 2111–2121 (2008).

    Google Scholar 

20. Daneshmandi, L. et al. Emergence of the stem cell secretome in regenerative engineering. Trends Biotechnol. 38, 1373–1384 (2020).

    Google Scholar 

21. Kwon, J. W. et al. Mesenchymal stem cell-derived secretomes-enriched alginate/ extracellular matrix hydrogel patch accelerates skin wound healing. Biomater. Res. 27, 107 (2023).

    Google Scholar 

22. Park, S. R. et al. Stem cell secretome and its effect on cellular mechanisms relevant to wound healing. Mol. Ther. 26, 606–617 (2018).

    Google Scholar 

23. Compagna, R. et al. Cell therapy in patients with critical limb ischemia. Stem Cells Int. 2015, 931420 (2015).

    Google Scholar 

24. Hussein, E. A. Stem cell therapy for vascular disorders. Vasc. Endovasc. Rev. 1, 17-21 (2018).

25. Cartland S. P. et al. The generation of stable microvessels in ischemia is mediated by endothelial cell derived TRAIL. Sci. Adv. 10, eadn8760 (2024).

26. Pittenger, M. F. et al. Mesenchymal stem cell perspective: cell biology to clinical progress. Npj Regen. Med. 4, 22 (2019).

    Google Scholar 

27. Benabid, A. & Peduto, L. Mesenchymal perivascular cells in immunity and disease. Curr. Opin. Immunol. 64, 50–55 (2020).

    Google Scholar 

28. Lee, H. Huh, Y. H. & Kang, K. T. Mesenchymal stem cells potentiate the vasculogenic capacity of endothelial colony-forming cells under hyperglycemic conditions. Life 12, 469 (2022).

29. Iqbal, F. et al. Combination human umbilical cord perivascular and endothelial colony forming cell therapy for ischemic cardiac injury. Npj Regen. Med. 8, 45 (2023).

    Google Scholar 

30. Rojas-Torres, M. et al. Unraveling the differential mechanisms of revascularization promoted by MSCs & ECFCs from adipose tissue or umbilical cord in a murine model of critical limb-threatening ischemia. J. Biomed. Sci. 31, 71 (2024).

    Google Scholar 

31. Barros Ferreira, L. et al. Effects of tumor necrosis factor-α and interleukin-1β on human retinal endothelial cells. Cytokine 173, 156407 (2024).

    Google Scholar 

32. Kim, D. Y. et al. Substance P ameliorates TNF-α-mediated impairment of human aortic vascular cells in vitro. Clin. Exp. Pharmacol. Physiol. 48, 1288–1297 (2021).

    Google Scholar 

33. González-Flores, D., Rodríguez, A. B. & Pariente, J. A. TNFα-induced apoptosis in human myeloid cell lines HL-60 and K562 is dependent of intracellular ROS generation. Mol. Cell Biochem. 390, 281–287 (2014).

    Google Scholar 

34. Honkura, N. et al. Intravital imaging-based analysis tools for vessel identification and assessment of concurrent dynamic vascular events. Nat. Commun. 9, 2746 (2018).

    Google Scholar 

35. Thurston, G. et al. Angiogenesis in mice with chronic airway inflammation: strain-dependent differences. Am. J. Pathol. 153, 1099–1112 (1998).

    Google Scholar 

36. Zama, N. & Toda, S. Designer cell therapy for tissue regeneration. Inflamm. Regen. 44, 15 (2024).

    Google Scholar 

37. Iismaa, S. E. et al. Comparative regenerative mechanisms across different mammalian tissues. Npj Regen. Med. 3, 6 (2018).

    Google Scholar 

38. Sanz-Nogués, C. & O’Brien, T. MSCs isolated from patients with ischemic vascular disease have normal angiogenic potential. Mol. Ther. 22, 1888–1889 (2014).

    Google Scholar 

39. Kim, C. K. et al. Combination stem cell therapy using dental pulp stem cells and human umbilical vein endothelial cells for critical hindlimb ischemia. BMB Rep. 55, 336–341 (2022).

    Google Scholar 

40. Amani, S. et al. Angiogenic effects of cell therapy within a biomaterial scaffold in a rat hind limb ischemia model. Sci. Rep. 11, 20545 (2021).

    Google Scholar 

41. Kim, J. J. et al. Vascular regeneration and skeletal muscle repair induced by long-term exposure to SDF-1α derived from engineered mesenchymal stem cells after hindlimb ischemia. Exp. Mol. Med. 55, 2248–2259 (2023).

    Google Scholar 

42. Nammian, P. et al. Comparative analysis of mouse bone marrow and adipose tissue mesenchymal stem cells for critical limb ischemia cell therapy. Stem Cell Res. Ther. 12, 58 (2021).

    Google Scholar 

Download references