Life Extension Magazine®
Doctor presenting stem cell research on the body

Issue: Jan 2017

2016 Stem Cell Conferences

Shinya Yamanaka,MD,PhD (Director, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan) was involved in the world's first clinical trial of iPSCs, which cost about a million dollars, was very time-consuming and only resulted in treatment for one patient. Dr. Yamanaka has concluded that for the foreseeable future, well HLA-matched iPSCs from donors must be used rather than iPSCs derived from the intended patient.

By Ben Best, BS, Pharmacy.

Clinical Trial of iPSCs

Shinya Yamanaka,MD,PhD (Director, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan) was involved in the world's first clinical trial of iPSCs, which cost about a million dollars, was very time-consuming and only resulted in treatment for one patient. Dr. Yamanaka has concluded that for the foreseeable future, well HLA-matched iPSCs from donors must be used rather than iPSCs derived from the intended patient.1

Because HLAs differ so much between individuals, transplantation of an organ or tissue results in a strong immune system rejection in proportion to the HLA mis-match. But a reasonably good match of HLAs between an organ donor and an organ recipient can minimize the amount of immune suppressant drugs required. Close matching of three HLAs (HLA-A, HLA-B, and HLA-DR) have the strongest influence on whether a kidney transplant will be successful.2

Dr. Yamanaka wants to create banks of 140 different iPS Cell lines, which could provide a good match for 90% of the population of Japan (which is genetically very uniform). Each of the HLAs should be homozygous, meaning the same HLA type is inherited from both parents. To find the 140 ideal iPSC donors will require screening about 160,000 Japanese.3

Masayo Takahashi, MD, PhD (Project Leader, Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Japan) conducted the world's first clinical trial using iPSCs for regenerative medicine. More than 7% of those over age 75 lose the ability to read or recognize faces due to degeneration of the macula of the retina in the eye.4 Dr. Takahashi used skin cells from two people with macular degeneration to create iPSCs, which she differentiated into retinal cells.5

There are no standards for differentiating in such a way as to ensure that the cells do not become cancerous in the process. So she did extensive testing of the cells on laboratory mice to ensure that there was no chance of cancer.6 She generated sheets of cells, rather than use an artificial scaffold,7 and transplanted the cells into the first patient from whom the cells had been derived. The transplant halted the macular degeneration and improved the patient's vision.5 One year after surgery there was no sign that any of the transplanted cells had become cancerous.8

But Dr. Yamanaka's team detected mutations in the second patient's iPSCs as Dr. Takahashi was preparing to transplant them. Although there was no definitive evidence that the mutations would become cancerous, in the interest of safety, there was no second transplant.5 Together, the two cases had cost about a million dollars, and had taken ten months ― mostly due to cautious measures taken to avoid the possibility of cancer. This convinced Dr. Yamanaka that patient-derived iPSC therapy is not currently practical.

Koji Eto, MD, PhD (Professor, Department of Clinical Application, Kyoto University, Kyoto, Japan) has worked on the derivation of platelets from iPSCs. Platelets are blood components found only in mammals, and which stop bleeding by adhering to blood vessel walls. Patients with deficient platelets rely on transfusions from donors, but these transfusions generally result in harmful immune system reactions.9 Platelets derived from iPSCs would avoid this immune system incompatibility. Dr. Eto has been perfecting methods to derive platelets from iPSCs, but his major problem has been that the number of platelets he is able to derive is too low to be clinically useful.10,11

Experiments with iPSCs

Hideyuki Okano, MD, PhD (Professor and Dean, School of Medicine, Keio University, Tokyo, Japan) has been working to derive neural stem cells from iPSCs that can be used to treat spinal cord injuries. In deriving neural stem cells from iPSCs, Dr. Okano has taken great care to prevent them from becoming cancerous.12

Despite iPSCs coming from the patient for whom the neural stem cells are intended, there is still danger that imperfections in the differentiation process can lead to immune system rejection.12 Dr. Okano has restored motor function in spinal cord injury in mice by transplanting neural cells derived from human iPSCs into the mice.13 He has also treated spinal cord injury in monkeys using neural stem cells derived from human iPSCs.14  In neither experiment did cancer occur.

Guang-Hui Liu, PhD (Professor, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China) has derived iPSCs from patients suffering from a variety of disease conditions, and used those cells to better understand the molecular mechanisms causing those diseases. He has done this with Parkinson's Disease,15 Werner's Syndrome,16 xeroderma pigmentosum,17 and Hutchinson-Gilford progeria syndrome.18  With the latter syndrome, he was able to use gene therapy to correct the disease-causing mutation in the iPSCs (but only in cells, he has not attempted this in patients).19 He has also attempted to use gene therapy to correct mutations in cells from patients having Falconi Anemia.20

Treatment of Patients with MSCs

Katarina Le Blanc, MD, PhD (Professor of Clinical Stem Cell Research, Karolinska Institute, Stockholm, Sweden) has used bone-marrow derived mesenchymal stem cells (MSCs) to treat patients suffering from transplant-induced immune reactions who did not benefit from steroids.21 Whether the MSCs were HLA matched to the patient did not affect the outcome.21 MSCs inhibit the immune system.22 The number of MSCs are normally increased by expansion in tissue culture before being administered to patients. Dr. Le Blanc has found better therapeutic benefit from MSCs that have not been expanded too many times.23 Dr. Le Blanc has found that MSCs are an effective therapy to treat patients who have been newly diagnosed with type 1 diabetes.24

Shigeki Sugii, PhD (Group Leader, Fat Metabolism and Stem Cell Group, Singapore Bioimaging Corsortium, Singapore) has investigated the use of MSCs from fat deposits rather than from bone marrow. MSCs cells can be extracted from fat deposits through liposuction, whereas obtaining MSCs from bond marrow is much more painful and invasive.25 Moreover, MSCs are a thousand times more plentiful in fat than in bone marrow.26 Fat-derived MSCs more readily differentiate into bone or fat cells, whereas bone marrow derived MSCs more readily differentiate into cartilage cells.27 Fat-derived MSCs promote wound-healing.28

Dr. Sugii has found that MSCs from subcutaneous fat proliferate and differentiate better than MSCs from visceral fat26 and are less likely to cause metabolic abnormalities.29 Dr. Sugii has investigated the molecular mechanisms underlying these differences.30

Somatic Stem Cells in Muscle

Pura Munoz-Canoves, PhD (Research Professor, University Pompeu Fabra, Barcelona, Spain) attempts to find means of opposing the loss of muscle function contributing to frailty in the elderly. A young person will typically have twice the number of somatic muscle stem cells as an elderly person.31 Dr. Munoz-Canoves has found that a decline in autophagy in muscle stem cells is a main cause of their loss.32 Autophagy is the process by which defective proteins and organelles are removed from cells, thereby maintaining cell quality. Dr. Munoz-Canoves has shown that she can prevent age-associated decline in muscles of mice by administering to them the autophagy-inducing drug rapamycin.33

Cancer Stem Cells

Jonathan Pachter, PhD (Chief Scientific Officer; Verastem, Inc., Needham, Massachusetts) is attempting to cure cancer by killing cancer stem cells. Chemotherapy or radiation therapy often kills most cancer cells, but often the cancer recurs. Multiple myeloma, for example, recurs more often than not.34 Cancer stem cells are the suspected reason for this problem.35,36

Most cancer cells divide rapidly, so cancer and radiation therapy kill all rapidly dividing cells. Stem cells are characterized by infrequent division, the ability to create at least one copy of itself on division ("self-renewal") and the ability to differentiate into a specific cell type. Infrequent cell division would make cancer stem cells resistant to radiation and chemotherapy. Studies of cancer cells show that only a small percentage can form new tumors on transplantation, so these cells are believed to be cancer stem cells.35

Focal Adhesion Kinase (FAK) is an enzyme believed to promote cancer stem cell growth and migration. So using drugs to inhibit FAK is a strategy to suppress cancer stem cells.37 Dr. Pachter has used FAK inhibitors as well as other drugs to substantially inhibit cancer stem cells in mice as well as in cell cultures.38,39

Oxygen and Stem Cells

Heather O'Leary, PhD (Postdoctoral fellow, Indiana University School of Medicine, Indianapolis, Indiana) is concerned about the effects of oxygen on stem cells. Stem cells normally reside in a low-oxygen environment, but are typically harvested in air, which has a higher oxygen content. Counteracting the oxygen stress associated with stem cell harvesting produces better results.40 Dr. O'Leary has studied the molecular mechanisms reducing the quality of stem cells harvested in air.41

Badrul Yahaya, PhD (Head, Regenerative Medicine Cluster, University Sains Malaysia, Malaysia) wishes to use stem cells to treat Chronic Obstructive Pulmonary Disease (COPD, the fourth leading cause of death in the United States). COPD is caused by chronic exposure to noxious particulate matter (usually cigarette smoke), which obstructs airways and destroys air sacs in the lung.42 COPD could be treated with mesenchymal stem cells, which reduces lung inflammation.43 Dr. Yahaya has shown that fibroblast cells can be delivered to the lungs of rabbits as an aerosol without reduction of cell survival, but cancer cells did not survive.44 Cancer cells are similar to stem cells in that they exist in a low oxygen environment. Dr. O'Leary's work suggests that it will probably be necessary to counteract oxygen stress to deliver stem cells to the lungs as an aerosol to effectively treat COPD.


  1. Cyranoski D. Stem-cell pioneer banks on future therapies. Nature. 2012 Aug 9;488(7410):139.
  2. Taylor CJ, Bolton EM, Bradley JA. Immunological considerations for embryonic and induced pluripotent stem cell banking. Philos Trans R Soc Lond B Biol Sci. 2011 Aug 12;366(1575):2312-22.
  3. Okita K, Matsumura Y, Sato Y, Okada A, Morizane A, Okamoto S, Hong H, Nakagawa M, Tanabe K, Tezuka K, Shibata T, Kunisada T, Takahashi M, Takahashi J, Saji H, Yamanaka S. A more efficient method to generate integration-free human iPS cells. Nat Methods. 2011 May;8(5):409-12.
  4. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology. 1992 Jun;99(6):933-43.
  5. Scudellari M. How iPS cells changed the world. Nature. 2016 Jun 15;534(7607):310-2.
  6. Kanemura H, Go MJ, Shikamura M, Nishishita N, Sakai N, Kamao H, Mandai M, Morinaga C, Takahashi M, Kawamata S. Tumorigenicity studies of induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration. PLoS One. 2014 Jan 14;9(1):e85336.
  7. Kamao H, Mandai M, Okamoto S, Sakai N, Suga A, Sugita S, Kiryu J, Takahashi M. Characterization of human induced pluripotent stem cell-derived retinal pigment epithelium cell sheets aiming for clinical application. Stem Cell Reports. 2014 Jan 23;2(2):205-18.
  8. Takahashi M. [Retinal Cell Therapy Using iPS Cells]. Nippon Ganka Gakkai Zasshi. 2016 Mar;120(3):210-24; discussion 225. Japanese.
  9. Feng Q, Shabrani N, Thon JN, Huo H, Thiel A, Machlus KR, Kim K, Brooks J, Li F, Luo C, Kimbrel EA, Wang J, Kim KS, Italiano J, Cho J, Lu SJ, Lanza R. Scalable generation of universal platelets from human induced pluripotent stem cells. Stem Cell Reports. 2014 Nov 11;3(5):817-31.
  10. Nakamura S, Takayama N, Hirata S, Seo H, Endo H, Ochi K, Fujita K, Koike T, Harimoto K, Dohda T, Watanabe A, Okita K, Takahashi N, Sawaguchi A, Yamanaka S, Nakauchi H, Nishimura S, Eto K. Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells. Cell Stem Cell. 2014 Apr 3;14(4):535-48.
  11. Karagiannis P, Eto K. Manipulating megakaryocytes to manufacture platelets ex vivo. J Thromb Haemost. 2015 Jun;13 Suppl 1:S47-53.
  12. Okano H, Nakamura M, Yoshida K, Okada Y, Tsuji O, Nori S, Ikeda E, Yamanaka S, Miura K. Steps toward safe cell therapy using induced pluripotent stem cells. Circ Res. 2013 Feb 1;112(3):523-33.
  13. Kawabata S, et al. Grafted Human iPS Cell-Derived Oligodendrocyte Precursor Cells Contribute to Robust Remyelination of Demyelinated Axons after Spinal Cord Injury. Stem Cell Reports. 2016 Jan 12;6(1):1-8.
  14. Kobayashi Y, Okada Y, Itakura G, Iwai H, Nishimura S, Yasuda A, Nori S, Hikishima K, Konomi T, Fujiyoshi K, Tsuji O, Toyama Y, Yamanaka S, Nakamura M, Okano H. Pre-evaluated safe human iPSC-derived neural stem cells promote functional recovery after spinal cord injury in common marmoset without tumorigenicity. PLoS One. 2012;7(12):e52787.
  15. Liu GH, Qu J, Suzuki K, Nivet E, Li M, Montserrat N, Yi F, Xu X, Ruiz S, Zhang W, Wagner U, Kim A, Ren B, Li Y, Goebl A, Kim J, Soligalla RD, Dubova I, Thompson J, Yates J 3rd, Esteban CR, Sancho-Martinez I, Izpisua Belmonte JC.Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature. 2012 Nov 22;491(7425):603-7.
  16. Zhang W, et al. Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging.Science. 2015 Jun 5;348(6239):1160-3.
  17. Fu L, Xu X, Ren R, Wu J, Zhang W, Yang J, Ren X, Wang S, Zhao Y, Sun L, Yu Y, Wang Z, Yang Z, Yuan Y, Qiao J, Izpisua Belmonte JC, Qu J, Liu GH. Modeling xeroderma pigmentosum associated neurological pathologies with patients-derived iPSCs. Protein Cell. 2016 Mar;7(3):210-21.
  18. Liu GH, Barkho BZ, Ruiz S, Diep D, Qu J, Yang SL, Panopoulos AD, Suzuki K, Kurian L, Walsh C, Thompson J, Boue S, Fung HL, Sancho-Martinez I, Zhang K, Yates J 3rd, Izpisua Belmonte JC. Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome. Nature. 2011 Apr 14;472(7342):221-5.
  19. Liu GH, Suzuki K, Qu J, Sancho-Martinez I, Yi F, Li M, Kumar S, Nivet E, Kim J, Soligalla RD, Dubova I, Goebl A, Plongthongkum N, Fung HL, Zhang K, Loring JF, Laurent LC, Izpisua Belmonte JC. Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs. Cell Stem Cell. 2011 Jun 3;8(6):688-94.
  20. Liu GH, et al. Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs. Nat Commun. 2014 Jul 7;5:4330.
  21. Le Blanc K, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008 May 10;371(9624):1579-86.
  22. Le Blanc K, Mougiakakos D. Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol. 2012 Apr 25;12(5):383-96.
  23. Moll G, Rasmusson-Duprez I, von Bahr L, Connolly-Andersen AM, Elgue G, Funke L, Hamad OA, Lönnies H, Magnusson PU, Sanchez J, Teramura Y, Nilsson-Ekdahl K, Ringdén O, Korsgren O, Nilsson B, Le Blanc K. Are therapeutic human mesenchymal stromal cells compatible with human blood? Stem Cells. 2012 Jul;30(7):1565-74.
  24. Carlsson PO, Schwarcz E, Korsgren O, Le Blanc K. Preserved β-cell function in type 1 diabetes by mesenchymal stromal cells. Diabetes. 2015 Feb;64(2):587-92.
  25. Nordberg RC, Loboa EG. Our Fat Future: Translating Adipose Stem Cell Therapy. Stem Cells Transl Med. 2015 Sep;4(9):974-9.
  26. Ong WK, Tan CS, Chan KL, Goesantoso GG, Chan XH, Chan E, Yin J, Yeo CR, Khoo CM, So JB, Shabbir A, Toh SA, Han W, Sugii S. Identification of specific cell-surface markers of adipose-derived stem cells from subcutaneous and visceral fat depots. Stem Cell Reports. 2014 Feb 6;2(2):171-9.
  27. Rider DA, Dombrowski C, Sawyer AA, Ng GH, Leong D, Hutmacher DW, Nurcombe V, Cool SM. Autocrine fibroblast growth factor 2 increases the multipotentiality of human adipose-derived mesenchymal stem cells. Stem Cells. 2008 Jun;26(6):1598-608.
  28. Lim MH, Ong WK, Sugii S. The current landscape of adipose-derived stem cells in clinical applications. Expert Rev Mol Med. 2014 May 7;16:e8.
  29. Ong WK, Sugii S. Adipose-derived stem cells: fatty potentials for therapy.Int J Biochem Cell Biol. 2013 Jun;45(6):1083-6.
  30. Takeda K, Sriram S, Chan XH, Ong WK, Yeo CR, Tan B, Lee SA, Kong KV, Hoon S, Jiang H, Yuen JJ, Perumal J, Agrawal M, Vaz C, So J, Shabbir A, Blaner WS, Olivo M, Han W, Tanavde V, Toh SA, Sugii S. Retinoic Acid Mediates Visceral-Specific Adipogenic Defects of Human Adipose-Derived Stem Cells. Diabetes. 2016 May;65(5):1164-78.
  31. Sousa-Victor P, García-Prat L, Serrano AL, Perdiguero E, Muñoz-Cánoves P. Muscle stem cell aging: regulation and rejuvenation. Trends Endocrinol Metab. 2015 Jun;26(6):287-96.
  32. García-Prat L, Martínez-Vicente M, Muñoz-Cánoves P. Autophagy: a decisive process for stemness. Oncotarget. 2016 Mar 15;7(11):12286-8.
  33. García-Prat L, Martínez-Vicente M, Perdiguero E, Ortet L, Rodríguez-Ubreva J, Rebollo E, Ruiz-Bonilla V, Gutarra S, Ballestar E, Serrano AL, Sandri M, Muñoz-Cánoves P. Autophagy maintains stemness by preventing senescence. Nature. 2016 Jan 7;529(7584):37-42.
  34. Giralt S, et al. American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplantation in Patients with Relapsed Multiple Myeloma. Biol Blood Marrow Transplant. 2015 Dec;21(12):2039-51.
  35. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001 Nov 1;414(6859):105-11.
  36. Panni RZ, Linehan DC, Denardo DG. Tumor-infiltrating macrophages, cancer stem cells and therapeutic responses. Oncotarget. 2012 Dec;3(12):1497-8.
  37. Luo M, Fan H, Nagy T, Wei H, Wang C, Liu S, Wicha MS, Guan JL. Mammary epithelial-specific ablation of the focal adhesion kinase suppresses mammary tumorigenesis by affecting mammary cancer stem/progenitor cells. Cancer Res. 2009 Jan 15;69(2):466-74.
  38. Serrels A, Lund T, Serrels B, Byron A, McPherson RC, von Kriegsheim A, Gómez-Cuadrado L, Canel M, Muir M, Ring JE, Maniati E, Sims AH, Pachter JA, Brunton VG, Gilbert N, Anderton SM, Nibbs RJ, Frame MC. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell. 2015 Sep 24;163(1):160-73.
  39. Kolev VN, Wright QG, Vidal CM, Ring JE, Shapiro IM, Ricono J, Weaver DT, Padval MV, Pachter JA, Xu Q. PI3K/mTOR dual inhibitor VS-5584 preferentially targets cancer stem cells. Cancer Res. 2015 Jan 15;75(2):446-55.
  40. Broxmeyer HE, O'Leary HA, Huang X, Mantel C. The importance of hypoxia and extra physiologic oxygen shock/stress for collection and processing of stem and progenitor cells to understand true physiology/pathology of these cells ex vivo. Curr Opin Hematol. 2015 Jul;22(4):273-8.
  41. Mantel CR, O'Leary HA, et al. Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock. Cell. 2015 Jun 18;161(7):1553-65.
  42. Houghton AM. Mechanistic links between COPD and lung cancer. Nat Rev Cancer. 2013 Apr;13(4):233-45.
  43. Weiss DJ. Concise review: current status of stem cells and regenerative medicine in lung biology and diseases. Stem Cells. 2014 Jan;32(1):16-25.
  44. Kardia E, Yusoff NM, Zakaria Z, Yahaya B. Aerosol-based delivery of fibroblast cells for treatment of lung diseases. J Aerosol Med Pulm Drug Deliv.2014 Feb;27(1):30-4.