Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Translational strategies and challenges in regenerative medicine

Abstract

The scientific community is currently witnessing substantial strides in understanding stem cell biology in humans; however, major disappointments in translating this knowledge into medical therapies are flooding the field as well. Despite these setbacks, investigators are determined to better understand the caveats of regeneration, so that major pathways of repair and regrowth can be exploited in treating aged and diseased tissues. Last year, in an effort to contribute to this burgeoning field, Nature Medicine, in collaboration with the Volkswagen Foundation, organized a meeting with a panel of experts in regenerative medicine to identify the most pressing challenges, as well as the crucial strategies and stem cell concepts that can best help advance the translational regenerative field. Here some experts who participated in the meeting provide an outlook at some of those key issues and concepts.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

References

  1. Schofield, R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4, 7–25 (1978).

    CAS  PubMed  Google Scholar 

  2. Daley, G.Q. The promise and perils of stem cell therapeutics. Cell Stem Cell 10, 740–749 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Conboy, I.M., Conboy, M.J., Smythe, G.M. & Rando, T.A. Notch-mediated restoration of regenerative potential to aged muscle. Science 302, 1575–1577 (2003).

    CAS  Article  PubMed  Google Scholar 

  4. van Praag, H., Kempermann, G. & Gage, F.H. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci. 2, 266–270 (1999).

    CAS  Article  PubMed  Google Scholar 

  5. Trejo, J.L., Carro, E. & Torres-Aleman, I. Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J. Neurosci. 21, 1628–1634 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Fabel, K. et al. VEGF is necessary for exercise-induced adult hippocampal neurogenesis. Eur. J. Neurosci. 18, 2803–2812 (2003).

    Article  PubMed  Google Scholar 

  7. Li, W., Li, K., Wei, W. & Ding, S. Chemical approaches to stem cell biology and therapeutics. Cell Stem Cell 13, 270–283 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Sato, T. & Clevers, H. Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science 340, 1190–1194 (2013).

    CAS  Article  PubMed  Google Scholar 

  9. Watt, F.M. & Hogan, B.L. Out of Eden: stem cells and their niches. Science 287, 1427–1430 (2000).

    CAS  Article  PubMed  Google Scholar 

  10. Watt, F.M. & Huck, W.T. Role of the extracellular matrix in regulating stem cell fate. Nat. Rev. Mol. Cell Biol. 14, 467–473 (2013).

    CAS  Article  PubMed  Google Scholar 

  11. Calvi, L.M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003).

    CAS  Article  PubMed  Google Scholar 

  12. Friedman, S.L., Sheppard, D., Duffield, J.S. & Violette, S. Therapy for fibrotic diseases: nearing the starting line. Sci. Transl. Med. 5, 167sr1 (2013).

    Article  PubMed  Google Scholar 

  13. Engler, A.J., Sen, S., Sweeney, H.L. & Discher, D.E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006).

    CAS  Article  PubMed  Google Scholar 

  14. Huang, N.F. & Li, S. Regulation of the matrix microenvironment for stem cell engineering and regenerative medicine. Ann. Biomed. Eng. 39, 1201–1214 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Turner, N.J. & Badylak, S.F. Biologic scaffolds for musculotendinous tissue repair. Eur. Cell. Mater. 25, 130–143 (2013).

    CAS  Article  PubMed  Google Scholar 

  16. Wong, V.W., Levi, B., Rajadas, J., Longaker, M.T. & Gurtner, G.C. Stem cell niches for skin regeneration. Int. J. Biomater. 2012, 926059 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Peerani, R. & Zandstra, P.W. Enabling stem cell therapies through synthetic stem cell-niche engineering. J. Clin. Invest. 120, 60–70 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Gómez-Gaviro, M.V., Lovell-Badge, R., Fernandez-Aviles, F. & Lara-Pezzi, E. The vascular stem cell niche. J. Cardiovasc. Transl. Res. 5, 618–630 (2012).

    Article  PubMed  Google Scholar 

  19. Palmer, T.D., Willhoite, A.R. & Gage, F.H. Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425, 479–494 (2000).

    CAS  Article  PubMed  Google Scholar 

  20. Ma, J. et al. Concise review: cell-based strategies in bone tissue engineering and regenerative medicine. Stem Cells Transl. Med. 3, 98–107 (2014).

    CAS  Article  PubMed  Google Scholar 

  21. Suda, T., Takubo, K. & Semenza, G.L. Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell 9, 298–310 (2011).

    CAS  Article  PubMed  Google Scholar 

  22. Titmarsh, D.M., Chen, H., Glass, N.R. & Cooper-White, J.J. Concise review: microfluidic technology platforms: poised to accelerate development and translation of stem cell-derived therapies. Stem Cells Transl. Med. 3, 81–90 (2014).

    Article  PubMed  Google Scholar 

  23. Conboy, I.M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005).

    CAS  Article  PubMed  Google Scholar 

  24. Villeda, S.A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Villeda, S.A. et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat. Med. 20, 659–663 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Katsimpardi, L. et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344, 630–634 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Elabd, C. et al. Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration. Nat. Commun. 5, 4082 (2014).

    CAS  Article  PubMed  Google Scholar 

  28. Maus, M.V. et al. Adoptive immunotherapy for cancer or viruses. Annu. Rev. Immunol. 32, 189–225 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Tebas, P. et al. N. Engl. J. Med. 370, 901–910 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Cutler, C. et al. Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation. Blood 122, 3074–3081 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Christopherson, K.W., Hangoc, G., Mantel, C.R. & Broxmeyer, H.E. Modulation of hematopoietic stem cell homing and engraftment by CD26. Science 305, 1000–1003 (2004).

    CAS  Article  PubMed  Google Scholar 

  32. Chinnadurai, R., Copland, I.B., Patel, S.R. & Galipeau, J. IDO-independent suppression of T cell effector function by IFN-γ–licensed human mesenchymal stromal cells. J. Immunol. 192, 1491–1501 (2014).

    CAS  Article  PubMed  Google Scholar 

  33. Seeger, F.H., Zeiher, A.M. & Dimmeler, S. MicroRNAs in stem cell function and regenerative therapy of the heart. Arterioscler. Thromb. Vasc. Biol. 33, 1739–1746 (2013).

    CAS  Article  PubMed  Google Scholar 

  34. Liles, W.C. et al. Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood 102, 2728–2730 (2003).

    CAS  Article  PubMed  Google Scholar 

  35. Zaruba, M.-M. et al. Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell 4, 313–323 (2009).

    CAS  Article  PubMed  Google Scholar 

  36. Broxmeyer, H.E. et al. Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis. Nat. Med. 18, 1786–1796 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Kragl, M. et al. Cells keep a memory of their tissue origin during axolotl limb regeneration. Nature 460, 60–65 (2009).

    CAS  Article  PubMed  Google Scholar 

  38. Efe, J.A. et al. Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nat. Cell Biol. 13, 215–222 (2011).

    CAS  Article  PubMed  Google Scholar 

  39. Wang H. et al. Small molecules enable cardiac reprogramming of mouse fibroblasts with a single factor, Oct4. Cell Rep. 6, 951–960 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Wang, F. et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340, 622–626 (2013).

    CAS  Article  PubMed  Google Scholar 

  41. Baker, D.J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Zhang, Q. et al. Small-molecule synergist of the Wnt/β-catenin signaling pathway. Proc. Natl. Acad. Sci. USA 104, 7444–7448 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Gu, E., Chen, W.Y., Gu, J., Burridge, P. & Wu, J.C. Molecular imaging of stem cells: tracking survival, biodistribution, tumorigenicity, and immunogenicity. Theranostics 2, 335–345 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. van Laake, L.W., Passier, R., Doevendans, P.A. & Mummery, C.L. Human embryonic stem cell-derived cardiomyocytes and cardiac repair in rodents. Circ. Res. 102, 1008–1010 (2008).

    CAS  Article  PubMed  Google Scholar 

  45. Rosado-de-Castro, P.H. et al. Biodistribution of bone marrow mononuclear cells after intra-arterial or intravenous transplantation in subacute stroke patients. Regen. Med. 8, 145–155 (2013).

    CAS  Article  PubMed  Google Scholar 

  46. Mohsin, S. et al. Human cardiac progenitor cells engineered with Pim-I kinase enhance myocardial repair. J. Am. Coll. Cardiol. 60, 1278–1287 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Ghadge, S.K., Mühlstedt, S., Ozcelik, C. & Bader, M. SDF-1α as a therapeutic stem cell homing factor in myocardial infarction. Pharmacol. Ther. 129, 97–108 (2011).

    CAS  Article  PubMed  Google Scholar 

  48. Frey, N. & Olson, E.N. Cardiac hypertrophy: the good, the bad, and the ugly. Annu. Rev. Physiol. 65, 45–79 (2003).

    CAS  Article  PubMed  Google Scholar 

  49. Lee, A.S., Tang, C., Rao, M.S., Weissman, I.L. & Wu, J.C. Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies. Nat. Med. 19, 998–1004 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Severs, N.J., Bruce, A.F., Dupont, E. & Rothery, S. Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc. Res. 80, 9–19 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. Li, F. et al. Neuroinflammation and cell therapy for Parkinson's disease. Front. Biosci. (schol. ed.) 3, 1407–1420 (2011).

    Article  Google Scholar 

  52. Hu, J. et al. Endothelial cell–derived angiopoietin-2 controls liver regeneration as a spatiotemporal rheostat. Science 343, 416–419 (2014).

    CAS  Article  PubMed  Google Scholar 

  53. Ding, B.S. et al. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 505, 97–102 (2014).

    Article  PubMed  Google Scholar 

  54. Kang, T.W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011).

    CAS  Article  PubMed  Google Scholar 

  55. Katsimpardi, L. et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344, 630–634 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. Segers, V.F. & Lee, R.T. Biomaterials to enhance stem cell function in the heart. Circ. Res. 109, 910–922 (2011).

    CAS  Article  PubMed  Google Scholar 

  57. Dimmeler, S. & Leri, A. Aging and disease as modifiers of efficacy of cell therapy. Circ. Res. 102, 1319–1330 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Xu, Q. et al. Micro-RNA-34a contributes to the impaired function of bone marrow-derived mononuclear cells from patients with cardiovascular disease. J. Am. Coll. Cardiol. 59, 2107–2117 (2012).

    CAS  Article  PubMed  Google Scholar 

  59. Trounson, A., Baum, E., Gibbons, D. & Tekamp-Olson, P. Developing a model for successful translation of stem cell therapies. Cell Stem Cell 6, 513–516 (2010).

    CAS  Article  PubMed  Google Scholar 

  60. Trounson, A. in Stem Cells Handbook, 2nd edn. (ed. Sell, S.) 377–389 (Springer, 2013).

    Book  Google Scholar 

  61. Nowbar, A.N. et al. Discrepancies in autologous bone marrow stem cell and enhancement of ejection fraction (DAMASCENE): weighted regression and meta-analysis. Br. Med. J. 348, g2688 (2014).

    Article  Google Scholar 

  62. Figueroa, F.E., Carrión, F., Villanueva, S. & Khoury, M. Mesenchymal stem cell treatment for autoimmune diseases: a critical review. Biol. Res. 45, 269–277 (2012).

    Article  PubMed  Google Scholar 

  63. Ren, G. et al. Concise review: mesenchymal stem cells and translational medicine: emerging issues. Stem Cells Transl. Med. 1, 51–58 (2012).

    CAS  Article  PubMed  Google Scholar 

  64. California Institute for Regenerative Medicine. Cell therapies for Parkinson's Disease from discovery to clinic. (CIRM, 2013). http://www.cirm.ca.gov/sites/default/files/files/about_cirm/PD_Workshop_WP__10-10-13.pdf

  65. Li, M., Suzuki, K., Kim, N.Y., Liu, G.H. & Izpisua Belmonte, J.C. A cut above the rest: targeted genome editing technologies in human pluripotent stem cells. J. Biol. Chem. 289, 4594–4599 (2014).

    CAS  Article  PubMed  Google Scholar 

  66. Bellin, M., Marchetto, M.C., Gage, F.H. & Mummery, C.L. Induced pluripotent stem cells: the new patient? Nat. Rev. Mol. Cell Biol. 13, 713–726 (2012).

    Article  PubMed  Google Scholar 

  67. Chong, J.J.H. et al. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 510, 273–277 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Turner, M. et al. Towards the development of a global induced pluripotent stem cell library. Cell Stem Cell 13, 382–384 (2013).

    CAS  Article  PubMed  Google Scholar 

  69. Rong, Z. et al. An effective approach to prevent immune rejection of human ESC-derived allografts. Cell Stem Cell 14, 121–130 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. Schulz, T.C. et al. A scalable system for production of functional pancreatic progenitors from human embryonic stem cells. PLoS ONE 7, e37004 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. Bara, J.J., Richards, R.G., Alini, M. & Stoddard, M.J. Bone marrow-derived mesenchymal stem cells change phenotype following in vitro culture: implications for basic research and the clinic. Stem Cells 32, 1713–1723 (2014).

    CAS  Article  PubMed  Google Scholar 

  72. Ginsberg, M. et al. Efficient direct reprogramming of mature amniotic cells into endothelial cells by ETS factors and TGFβ suppression. Cell 151, 559–575 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. Bharti, K. et al. Developing cellular therapies for retinal degenerative diseases. Invest. Ophthalmol. Vis. Sci. 55, 1191–1202 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Zhang, D. et al. Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes. Biomaterials 34, 5813–5820 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. Fu, J.-D. et al. Direct reprogramming of human fibroblasts towards a cardiomyocyte-like state. Stem Cell Rep. 1, 235–247 (2013).

    CAS  Article  Google Scholar 

  76. Ruckh, J.M. et al. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 10, 96–103 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. van Deursen, J.M. The role of senescent cells in ageing. Nature 509, 439–446 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. David, D.C. Aging and the aggregating proteome. Front. Genet. 3, 247 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Stefanie Dimmeler, Sheng Ding, Thomas A Rando or Alan Trounson.

Ethics declarations

Competing interests

S. Dimmeler is founder of and adviser to t2Cure GmbH and adviser to miRagen Therapeutics. The other authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Dimmeler, S., Ding, S., Rando, T. et al. Translational strategies and challenges in regenerative medicine. Nat Med 20, 814–821 (2014). https://doi.org/10.1038/nm.3627

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3627

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing