Skip to main content

Introduction and Basic Concepts in Stem Cell Research and Therapy: The Facts and the Hype

  • Chapter
  • First Online:
Regenerative Medicine and Stem Cell Biology

Abstract

Stem cells play critical roles in biological processes, such as tissue development and homeostasis; they also present great promise toward promoting breakthroughs in regenerative medicine. Stem cells may be used to explore disease modeling, for screening of new drugs, and for the treatment of intractable diseases. The transition of stem cell biology from basic research to clinical applications has involved both hope and hype. Indeed, premature application of stem cell therapy as a clinical “cure-all” without sufficient experimental, preclinical, or clinical research has led to shady practices and false promises. While this is, understandably, fueled by patients in need of cures for unmanageable chronic and degenerative diseases, hype-based practices have promoted the spread of clinically unproven therapies. These therapies may have no impact on the disease process or may result in devastating outcomes. Stem cells may ultimately have the capacity to treat intractable diseases, including diabetes, cardiovascular disorders, metabolic disorders, hematopoietic disorders, and immunodeficiency disorders. However, and despite significant promise, there remains a need to elucidate numerous misunderstandings associated with stem cell therapy and to define the current barriers and obstacles faced by those involved in stem cell research and its therapeutic applications. As such, the main goal of this chapter was to provide the reader with an overview of basic concepts in stem cell research and review the facts and the unfortunate hype with respect to current clinical applications and disease treatments.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 69.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 89.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

(ACI):

Autologous Chondrocyte Implantation

(ADSCs):

Adipose-derived stem cells

(ALL):

Acute Lymphoblastic Leukemia

(AMD):

Age-related Macular Degeneration

(AML):

Acute Myeloid Leukemia

(BM):

Bone Marrow

(BM-HSCs):

Bone Marrow Hematopoietic Stem Cells

(BM-MSCs):

Bone Marrow Mesenchymal Stem Cells

(CAR):

Chimeric Antigen Receptor

(CBT):

Cord Blood Transplantation

(CFU-F):

Colony Forming-Unit Fibroblast

(CLL):

Chronic Lymphoblastic Leukemia

(CLP):

Common Lymphoid Progenitor

(CML):

Chronic Myeloid Leukemia

(DLI):

Donor Leukocyte Infusion

(DM):

Diabetes Mellitus

(DMT1):

Type 1 Diabetes Mellitus

(DMT2):

Type 2 Diabetes Mellitus

(ECM):

Extracellular Matrix

(ESCs):

Embryonic stem cells

(FTSG):

Full-thickness Skin Graft

(G-CSF):

Granulocyte Colony-stimulating Factor

(GvHD):

Graft versus Host Disease

(GVL):

Graft Versus Leukemia

(HSCs):

Hematopoietic Stem Cells

(HSCT):

Hematopoietic Stem Cell Transplantation

(HSPCs):

Hematopoietic Stem/Progenitor Cells

(iPSCs):

Induced Pluripotent Stem Cells

(ISSCR):

International Society for Stem Cell Research

(MS):

Multiple Sclerosis

(MSCs):

Mesenchymal Stem Cells

(NSCs):

Neural Stem Cells

(OA):

Osteoarthritis

(PB):

Peripheral Blood

(PD):

Parkinson’s Disease

(PRP):

Platelet-rich Plasma

(RIC):

Reduced-intensity Conditioning

(RPE):

Retinal Pigment Epithelial

(SCNT):

Somatic Cell Nuclear Transfer

(STSG):

Split-thickness Skin Graft

(UCB):

Umbilical Cord Blood

(UC-HSCs):

Umbilical Cord Hematopoietic Stem Cells

(UC-MSCs):

Umbilical Cord Mesenchymal Stem Cells

References

  1. Becker AJ, McCulloch EA, Till JE. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature. 1963;197(4866):452–4.

    Article  CAS  PubMed  Google Scholar 

  2. McCulloch EA, Till JE. The radiation sensitivity of normal mouse bone marrow cells, determined by quantitative marrow transplantation into irradiated mice. Radiat Res. 1960;13(1):115–25.

    Article  CAS  PubMed  Google Scholar 

  3. Till JE, McCulloch EA. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res. 1961;14(2):213–22.

    Article  CAS  PubMed  Google Scholar 

  4. Khanh VC, Zulkifli AF, Tokunaga C, Yamashita T, Hiramatsu Y, Ohneda O. Aging impairs beige adipocyte differentiation of mesenchymal stem cells via the reduced expression of Sirtuin 1. Biochem Biophys Res Commun. 2018;500(3):682–90.

    Article  CAS  PubMed  Google Scholar 

  5. Cui H, Tang D, Garside GB, Zeng T, Wang Y, Tao Z, et al. Wnt signaling mediates the aging-induced differentiation impairment of intestinal stem cells. Stem Cell Rev Rep. 2019;15(3):448–55.

    Article  CAS  PubMed  Google Scholar 

  6. Huang T, Liu R, Fu X, Yao D, Yang M, Liu Q, et al. Aging reduces an ERRalpha-directed mitochondrial glutaminase expression suppressing glutamine anaplerosis and osteogenic differentiation of mesenchymal stem cells. Stem Cells. 2017;35(2):411–24.

    Article  CAS  PubMed  Google Scholar 

  7. Iismaa SE, Kaidonis X, Nicks AM, Bogush N, Kikuchi K, Naqvi N, et al. Comparative regenerative mechanisms across different mammalian tissues. npj Regenerative Med. 2018;3(1):6.

    Article  Google Scholar 

  8. Tarkowski AK, Wróblewska J. Development of blastomeres of mouse eggs isolated at the 4- and 8-cell stage. J Embryol Exp Morpholog. 1967;18(1):155–80.

    CAS  Google Scholar 

  9. Tarkowski AK. Experiments on the development of isolated blastomeres of mouse eggs. Nature. 1959;184(4695):1286–7.

    Article  CAS  PubMed  Google Scholar 

  10. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145–7.

    Article  CAS  PubMed  Google Scholar 

  11. Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991;9(5):641–50.

    Article  CAS  PubMed  Google Scholar 

  12. Bryder D, Rossi DJ, Weissman IL. Hematopoietic stem cells: the paradigmatic tissue-specific stem cell. Am J Pathol. 2006;169(2):338–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Warner K, Luther C, Takei F. Lymphoid progenitors in normal mouse lymph nodes develop into NK cells and T cells in vitro and in vivo. Exp Hematol. 2012;40(5):401–6.

    Article  CAS  PubMed  Google Scholar 

  14. Alonso L, Fuchs E. Stem cells of the skin epithelium. Proc Natl Acad Sci. 2003;100(Suppl 1):11830–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xie JL, Li TZ, Qi SH, Huang B, Chen XG, Chen JD. A study of using tissue-engineered skin reconstructed by candidate epidermal stem cells to cover the nude mice with full-thickness skin defect. J Plast Reconstr Aesthet Surg. 2007;60(9):983–90.

    Article  PubMed  Google Scholar 

  16. Naldaiz-Gastesi N, Goicoechea M, Aragón IM, Pérez-López V, Fuertes-Alvarez S, Herrera-Imbroda B, et al. Isolation and characterization of myogenic precursor cells from human cremaster muscle. Sci Rep. 2019;9(1):3454.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. de Rooij DG. The nature and dynamics of spermatogonial stem cells. Development. 2017;144(17):3022–30.

    Article  PubMed  CAS  Google Scholar 

  18. Gurdon JB. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J Embryol Exp Morpholog. 1962;10(4):622–40.

    CAS  Google Scholar 

  19. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.

    Article  CAS  PubMed  Google Scholar 

  20. Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292(5819):154–6.

    Article  CAS  PubMed  Google Scholar 

  21. Murry CE, Keller G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell. 2008;132(4):661–80.

    Article  CAS  PubMed  Google Scholar 

  22. Vazin T, Freed WJ. Human embryonic stem cells: derivation, culture, and differentiation: a review. Restor Neurol Neurosci. 2010;28(4):589–603.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Mehta RH. Sourcing human embryos for embryonic stem cell lines: problems & perspectives. Indian J Med Res. 2014;140(Suppl 1):S106–11.

    PubMed  PubMed Central  Google Scholar 

  24. Council NR. Final Report of the National Academies’ Human Embryonic Stem Cell Research Advisory Committee and 2010 Amendments to the National Academies’ Guidelines for Human Embryonic Stem Cell Research. National Academies Press (US); 2010.

    Google Scholar 

  25. de Wert G, Mummery C. Human embryonic stem cells: research, ethics and policy. Human Reproduct (Oxford, England). 2003;18(4):672–82.

    Article  Google Scholar 

  26. Colter DC, Sekiya I, Prockop DJ. Identification of a subpopulation of rapidly self-renewing and multipotential adult stem cells in colonies of human marrow stromal cells. Proc Natl Acad Sci USA. 2001;98(14):7841–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of Guinea-Pig bone marrow and spleen cells. Cell Prolif. 1970;3(4):393–403.

    Article  CAS  Google Scholar 

  28. Soleimani M, Nadri S. A protocol for isolation and culture of mesenchymal stem cells from mouse bone marrow. Nat Protoc. 2009;4(1):102–6.

    Article  CAS  PubMed  Google Scholar 

  29. Schneider S, Unger M, van Griensven M, Balmayor ER. Adipose-derived mesenchymal stem cells from liposuction and resected fat are feasible sources for regenerative medicine. Eur J Med Res. 2017;22(1):17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Di Scipio F, Sprio AE, Carere ME, Yang Z, Berta GN. A simple protocol to isolate, characterize, and expand dental pulp stem cells. In: Di Nardo P, Dhingra S, Singla DK, editors. Adult stem cells: methods and protocols. New York: Springer; 2017. p. 1–13.

    Google Scholar 

  31. Hatakeyama A, Uchida S, Utsunomiya H, Tsukamoto M, Nakashima H, Nakamura E, et al. Isolation and characterization of synovial Mesenchymal stem cell derived from hip joints: a comparative analysis with a matched control knee group. Stem Cells Int. 2017;2017:9312329.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Johansson CB, Momma S, Clarke DL, Risling M, Lendahl U, Frisén J. Identification of a neural stem cell in the adult mammalian central nervous system. Cell. 1999;96(1):25–34.

    Article  CAS  PubMed  Google Scholar 

  33. Gage FH. Mammalian neural stem cells. Science. 2000;287(5457):1433–8.

    Article  CAS  PubMed  Google Scholar 

  34. Lien BV, Tuszynski MH, Lu P. Astrocytes migrate from human neural stem cell grafts and functionally integrate into the injured rat spinal cord. Exp Neurol. 2019;314:46–57.

    Article  CAS  PubMed  Google Scholar 

  35. McLauchlan D, Robertson NP. Stem cells in the treatment of central nervous system disease. J Neurol. 2018;265(4):984–6.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ueno Y, Koizumi S, Yamagami M, Miura M, Taniguchi N. Characterization of hemopoietic stem cells (CFUc) in cord blood. Exp Hematol. 1981;9(7):716–22.

    CAS  PubMed  Google Scholar 

  37. Till J, McCulloch E. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res. 2012;178(2):AV3–7.

    Article  CAS  PubMed  Google Scholar 

  38. Broxmeyer HE, Douglas GW, Hangoc G, Cooper S, Bard J, English D, et al. Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells. Proc Natl Acad Sci U S A. 1989;86(10):3828–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Beeravolu N, McKee C, Alamri A, Mikhael S, Brown C, Perez-Cruet M, et al. Isolation and characterization of mesenchymal stromal cells from human umbilical cord and fetal placenta. J Vis Exp. 2017;122:55224.

    Google Scholar 

  40. Wu M, Zhang R, Zou Q, Chen Y, Zhou M, Li X, et al. Comparison of the biological characteristics of mesenchymal stem cells derived from the human placenta and umbilical cord. Sci Rep. 2018;8(1):1–9.

    Article  CAS  Google Scholar 

  41. Wouters G, Grossi S, Mesoraca A, Bizzoco D, Mobili L, Cignini P, et al. Isolation of amniotic fluid-derived mesenchymal stem cells. J Prenat Med. 2007;1(3):39–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Nishikawa S, Goldstein RA, Nierras CR. The promise of human induced pluripotent stem cells for research and therapy. Nat Rev Mol Cell Biol. 2008;9(9):725–9.

    Article  CAS  PubMed  Google Scholar 

  43. Reubinoff BE, Pera MF, Fong C-Y, Trounson A, Bongso A. Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol. 2000;18(4):399–404.

    Article  CAS  PubMed  Google Scholar 

  44. Deng Z-L, Sharff KA, Tang N, Song W-X, Luo J, Luo X, et al. Regulation of osteogenic differentiation during skeletal development. Front Biosci. 2008;13(1):2001–21.

    Article  CAS  PubMed  Google Scholar 

  45. Dai R, Wang Z, Samanipour R, Koo K-I, Kim K. Adipose-derived stem cells for tissue engineering and regenerative medicine applications. Stem Cells Int. 2016;2016:6737345.

    PubMed  PubMed Central  Google Scholar 

  46. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. the international society for cellular therapy position statement. Cytotherapy. 2006;8(4):315–7.

    Article  CAS  PubMed  Google Scholar 

  47. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917–20.

    Article  CAS  PubMed  Google Scholar 

  48. Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell. 2005;122(6):947–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Horwitz E, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, et al. Clarification of the nomenclature for MSC: the international society for cellular therapy position statement. Cytotherapy. 2005;7(5):393–5.

    Article  CAS  PubMed  Google Scholar 

  50. Ahmed TA, Shousha WG, Abdo SM, Mohamed I, El-Badri N. Human adipose-derived pericytes: biological characterization and reprogramming into induced pluripotent stem cells. Cell Physiol Biochem. 2020;54:271–86.

    CAS  PubMed  Google Scholar 

  51. Ilic D, Ogilvie C. Concise review: human embryonic stem cells—what have we done? What are we doing? Where are we going? Stem Cells. 2017;35(1):17–25.

    Article  CAS  PubMed  Google Scholar 

  52. Perez-Cunningham J, Ames E, Smith RC, Peter AK, Naidu R, Nolta JA, et al. Natural killer cell subsets differentially reject embryonic stem cells based on licensing. Transplantation. 2014;97(10):992–8.

    Article  CAS  PubMed  Google Scholar 

  53. Ng AP, Alexander WS. Haematopoietic stem cells: past, present and future. Cell Death Dis. 2017;3(1):1–4.

    Google Scholar 

  54. Mosaad YM. Immunology of hematopoietic stem cell transplant. Immunol Investig. 2014;43(8):858–87.

    Article  CAS  Google Scholar 

  55. Morandi F, Raffaghello L, Bianchi G, Meloni F, Salis A, Millo E, et al. Immunogenicity of human mesenchymal stem cells in HLA-class I-restricted T-cell responses against viral or tumor-associated antigens. Stem Cells. 2008;26(5):1275–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kruse V, Hamann C, Monecke S, Cyganek L, Elsner L, Hübscher D, et al. Human induced pluripotent stem cells are targets for allogeneic and autologous natural killer (NK) cells and killing is partly mediated by the activating NK receptor DNAM-1. PLoS One. 2015;10(5):e0125544.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Volarevic V, Markovic BS, Gazdic M, Volarevic A, Jovicic N, Arsenijevic N, et al. Ethical and safety issues of stem cell-based therapy. Int J Med Sci. 2018;15(1):36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zheng YL. Some ethical concerns about human induced pluripotent stem cells. Sci Eng Ethics. 2016;22(5):1277–84.

    Article  PubMed  Google Scholar 

  59. Kimbrel EA, Lanza R. Next-generation stem cells — ushering in a new era of cell-based therapies. Nat Rev Drug Discov. 2020;

    Google Scholar 

  60. Rubin LL, Haston KM. Stem cell biology and drug discovery. BMC Biol. 2011;9:42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wang Y, Yin P, Bian G-L, Huang H-Y, Shen H, Yang J-J, et al. The combination of stem cells and tissue engineering: an advanced strategy for blood vessels regeneration and vascular disease treatment. Stem Cell Res Ther. 2017;8(1):194.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Trounson A. New perspectives in human stem cell therapeutic research. BMC Med. 2009;7:29.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Zhang C-L, Huang T, Wu B-L, He W-X, Liu D. Stem cells in cancer therapy: opportunities and challenges. Oncotarget. 2017;8(43):75756–66.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Persons DA. The challenge of obtaining therapeutic levels of genetically modified hematopoietic stem cells in beta-thalassemia patients. Ann N Y Acad Sci. 2010;1202:69–74.

    Article  CAS  PubMed  Google Scholar 

  65. Yannaki E, Stamatoyannopoulos G. Hematopoietic stem cell mobilization strategies for gene therapy of beta thalassemia and sickle cell disease. Ann N Y Acad Sci. 2010;1202:59–63.

    Article  CAS  PubMed  Google Scholar 

  66. Porrata LF, Inwards DJ, Ansell SM, Micallef IN, Johnston PB, Villasboas JC, et al. Autograft immune content and survival in non-Hodgkin’s lymphoma: a post hoc analysis. Leuk Res. 2019;81:1–9.

    Article  CAS  PubMed  Google Scholar 

  67. Platzbecker U, Thiede C, Freiberg-Richter J, Röllig C, Helwig A, Schäkel U, et al. Early allogeneic blood stem cell transplantation after modified conditioning therapy during marrow aplasia: stable remission in high-risk acute myeloid leukemia. Bone Marrow Transplant. 2001;27(5):543–6.

    Article  CAS  PubMed  Google Scholar 

  68. Zhang J, Guan J, Niu X, Hu G, Guo S, Li Q, et al. Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. J Transl Med. 2015;13(1):49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Cristante AF, Barros-Filho TEP, Tatsui N, Mendrone A, Caldas JG, Camargo A, et al. Stem cells in the treatment of chronic spinal cord injury: evaluation of somatosensitive evoked potentials in 39 patients. Spinal Cord. 2009;47(10):733–8.

    Article  CAS  PubMed  Google Scholar 

  70. Lévesque M, Neuman T, Rezak M. Therapeutic microinjection of autologous adult human neural stem cells and differentiated neurons for Parkinson’s disease: five-year post-operative outcome. The Open Stem Cell Journal. 2009;1:20–9.

    Article  Google Scholar 

  71. Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, Kassis I, et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol. 2010;67(10):1187–94.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Álvaro-Gracia JM, Jover JA, García-Vicuña R, Carreño L, Alonso A, Marsal S, et al. Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis (Cx611): results of a multicentre, dose escalation, randomised, single-blind, placebo-controlled phase Ib/IIa clinical trial. Ann Rheum Dis. 2017;76(1):196–202.

    Article  PubMed  CAS  Google Scholar 

  73. García-Olmo D, García-Arranz M, Herreros D, Pascual I, Peiro C, Rodríguez-Montes JA. A phase I clinical trial of the treatment of Crohn’s fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum. 2005;48(7):1416–23.

    Article  PubMed  Google Scholar 

  74. Haller MJ, Wasserfall CH, McGrail KM, Cintron M, Brusko TM, Wingard JR, et al. Autologous umbilical cord blood transfusion in very young children with type 1 diabetes. Diab Care. 2009;32(11):2041–6.

    Article  Google Scholar 

  75. Patel AN, Henry TD, Quyyumi AA, Schaer GL, Anderson RD, Toma C, et al. Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial. Lancet (London, England). 2016;387(10036):2412–21.

    Article  CAS  Google Scholar 

  76. Siqueira RC, Messias A, Messias K, Arcieri RS, Ruiz MA, Souza NF, et al. Quality of life in patients with retinitis pigmentosa submitted to intravitreal use of bone marrow-derived stem cells (Reticell -clinical trial). Stem Cell Res Ther. 2015;6(1):29.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Schwartz SD, Regillo CD, Lam BL, Eliott D, Rosenfeld PJ, Gregori NZ, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet (London, England). 2015;385(9967):509–16.

    Article  Google Scholar 

  78. Maumus M, Manferdini C, Toupet K, Peyrafitte JA, Ferreira R, Facchini A, et al. Adipose mesenchymal stem cells protect chondrocytes from degeneration associated with osteoarthritis. Stem Cell Res. 2013;11(2):834–44.

    Article  CAS  PubMed  Google Scholar 

  79. Loeb DM, Hobbs RF, Okoli A, Chen AR, Cho S, Srinivasan S, et al. Tandem dosing of samarium-153 ethylenediamine tetramethylene phosphoric acid with stem cell support for patients with high-risk osteosarcoma. Cancer. 2010;116(23):5470–8.

    Article  PubMed  Google Scholar 

  80. Bordignon C. Stem-cell therapies for blood diseases. Nature. 2006;441(7097):1100–2.

    Article  CAS  PubMed  Google Scholar 

  81. Jaffe ES, Harris NL, Diebold J, Muller-Hermelink HK. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. A progress report. Am J Clin Pathol. 1999;111(1 Suppl 1):S8–12.

    CAS  PubMed  Google Scholar 

  82. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994;84(5):1361–92.

    Article  CAS  PubMed  Google Scholar 

  83. Isidro A, Seiler R, Seco M. Leukemia in Ancient Egypt: earliest case and state-of-the-art techniques for diagnosing generalized osteolytic lesions. Int J Osteoarchaeol. 2019;29

    Google Scholar 

  84. Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997–2002. Cancer Causes Control: CCC. 2008;19(4):379–90.

    Article  PubMed  Google Scholar 

  85. Farber S, Diamond LK. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med. 1948;238(23):787–93.

    Article  CAS  PubMed  Google Scholar 

  86. Miller DR. A tribute to Sidney Farber-- the father of modern chemotherapy. Br J Haematol. 2006;134(1):20–6.

    Article  PubMed  Google Scholar 

  87. Kharfan-Dabaja MA, Kumar A, Hamadani M, Stilgenbauer S, Ghia P, Anasetti C, et al. Clinical practice recommendations for use of allogeneic hematopoietic cell transplantation in Chronic Lymphocytic Leukemia on Behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2016;22(12):2117–25.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Dreger P, Schetelig J, Andersen N, Corradini P, van Gelder M, Gribben J, et al. Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents? Blood. 2014;124(26):3841–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Caballero D, García-Marco JA, Martino R, Mateos V, Ribera JM, Sarrá J, et al. Allogeneic transplant with reduced intensity conditioning regimens may overcome the poor prognosis of B-cell chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene and chromosomal abnormalities (11q- and 17p-). Clin Cancer Res. 2005;11(21):7757–63.

    Article  CAS  PubMed  Google Scholar 

  90. Moreno C, Villamor N, Colomer D, Esteve J, Martino R, Nomdedéu J, et al. Allogeneic stem-cell transplantation may overcome the adverse prognosis of unmutated VH gene in patients with chronic lymphocytic leukemia. J Clin Oncol. 2005;23(15):3433–8.

    Article  PubMed  Google Scholar 

  91. Henig I, Zuckerman T. Hematopoietic stem cell transplantation-50 years of evolution and future perspectives. Rambam Maimonides Med J. 2014;5(4):e0028-e.

    Article  Google Scholar 

  92. E Donnall Thomas (1920–2012). Bone marrow transplantation. 2013;48(1):1.

    Google Scholar 

  93. Savani BN, Mielke S, Reddy N, Goodman S, Jagasia M, Rezvani K. Management of relapse after allo-SCT for AML and the role of second transplantation. Bone Marrow Transplant. 2009;44(12):769–77.

    Article  CAS  PubMed  Google Scholar 

  94. Kolb H, Mittermuller J, Clemm C, Holler E, Ledderose G, Brehm G, et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood. 1990;76(12):2462–5.

    Article  CAS  PubMed  Google Scholar 

  95. Beilhack A, Schulz S, Baker J, Beilhack GF, Wieland CB, Herman EI, et al. In vivo analyses of early events in acute graft-versus-host disease reveal sequential infiltration of T-cell subsets. Blood. 2005;106(3):1113–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Nagler A, Slavin S, Varadi G, Naparstek E, Samuel S, Or R. Allogeneic peripheral blood stem cell transplantation using a fludarabine-based low intensity conditioning regimen for malignant lymphoma. Bone Marrow Transplant. 2000;25(10):1021–8.

    Article  CAS  PubMed  Google Scholar 

  97. Marks DI, Woo KA, Zhong X, Appelbaum FR, Bachanova V, Barker JN, et al. Unrelated umbilical cord blood transplant for adult acute lymphoblastic leukemia in first and second complete remission: a comparison with allografts from adult unrelated donors. Haematologica. 2014;99(2):322–8.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Gluckman E, Rocha V, Boyer-Chammard A, Locatelli F, Arcese W, Pasquini R, et al. Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med. 1997;337(6):373–81.

    Article  CAS  PubMed  Google Scholar 

  99. Scaradavou A, Brunstein CG, Eapen M, Le-Rademacher J, Barker JN, Chao N, et al. Double unit grafts successfully extend the application of umbilical cord blood transplantation in adults with acute leukemia. Blood. 2013;121(5):752–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ballen KK, Gluckman E, Broxmeyer HE. Umbilical cord blood transplantation: the first 25 years and beyond. Blood. 2013;122(4):491–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Rocha V, Gluckman E. Improving outcomes of cord blood transplantation: HLA matching, cell dose and other graft- and transplantation-related factors. Br J Haematol. 2009;147(2):262–74.

    Article  CAS  PubMed  Google Scholar 

  102. Herr AL, Kabbara N, Bonfim CM, Teira P, Locatelli F, Tiedemann K, et al. Long-term follow-up and factors influencing outcomes after related HLA-identical cord blood transplantation for patients with malignancies: an analysis on behalf of Eurocord-EBMT. Blood. 2010;116(11):1849–56.

    Article  CAS  PubMed  Google Scholar 

  103. Visani G, Lemoli R, Tosi P, Martinelli G, Testoni N, Ricci P, et al. Use of peripheral blood stem cells for autologous transplantation in acute myeloid leukemia patients allows faster engraftment and equivalent disease-free survival compared with bone marrow cells. Bone Marrow Transplant. 1999;24(5):467–72.

    Article  CAS  PubMed  Google Scholar 

  104. D’Souza A, Lee S, Zhu X, Pasquini M. Current use and trends in hematopoietic cell transplantation in the United States. Biol Blood Marrow Transplant. 2017;23(9):1417–21.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Wang X, Xiao Q, Wang Z, Feng WL. CAR-T therapy for leukemia: progress and challenges. Transl Res. 2017;182:135–44.

    Article  CAS  PubMed  Google Scholar 

  106. Ali S, Kjeken R, Niederlaender C, Markey G, Saunders TS, Opsata M, et al. The European medicines agency review of Kymriah (Tisagenlecleucel) for the treatment of acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Oncologist. 2020;25(2):e321–e7.

    Article  PubMed  Google Scholar 

  107. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA–guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337(6096):816–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Patmanathan SN, Gnanasegaran N, Lim MN, Husaini R, Fakiruddin KS, Zakaria Z. CRISPR/Cas9 in stem cell research: current application and future perspective. Curr Stem Cell Res Therapy. 2018;13(8):632–44.

    Article  CAS  Google Scholar 

  109. MacNeil S. Progress and opportunities for tissue-engineered skin. Nature. 2007;445(7130):874–80.

    Article  CAS  PubMed  Google Scholar 

  110. Groeber F, Holeiter M, Hampel M, Hinderer S, Schenke-Layland K. Skin tissue engineering--in vivo and in vitro applications. Adv Drug Deliv Rev. 2011;63(4–5):352–66.

    Article  CAS  PubMed  Google Scholar 

  111. Ragnell A. The secondary contracting tendency of free skin grafts; an experimental investigation on animals. Br J Plast Surg. 1952;5(1):6–24.

    Article  CAS  PubMed  Google Scholar 

  112. Blair VP, Brown JB. The use and uses of large split skin grafts of intermediate thickness. Plast Reconstr Surg. 1968;42(1):65–75.

    Article  Google Scholar 

  113. Johnson TM, Ratner D, Nelson BR. Soft tissue reconstruction with skin grafting. J Am Acad Dermatol. 1992;27(2):151–65.

    Article  CAS  PubMed  Google Scholar 

  114. Boyce ST, Lalley AL. Tissue engineering of skin and regenerative medicine for wound care. Burns & Trauma. 2018;6

    Google Scholar 

  115. Vig K, Chaudhari A, Tripathi S, Dixit S, Sahu R, Pillai S, et al. Advances in skin regeneration using tissue engineering. Int J Mol Sci. 2017;18(4):789.

    Article  PubMed Central  CAS  Google Scholar 

  116. Heimbach D, Luterman A, Burke J, Cram A, Herndon D, Hunt J, et al. Artificial dermis for major burns. A multi-center randomized clinical trial. Ann Surg. 1988;208(3):313–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Jansen LA, De Caigny P, Guay NA, Lineaweaver WC, Shokrollahi K. The evidence base for the acellular dermal matrix AlloDerm: a systematic review. Ann Plast Surg. 2013;70(5):587–94.

    Article  CAS  PubMed  Google Scholar 

  118. Larson KW, Austin CL, Thompson SJ. Treatment of a full-thickness burn injury with NovoSorb biodegradable temporizing matrix and RECELL autologous skin cell suspension: a case series. J Burn Care Res. 2020;41(1):215–9.

    Article  PubMed  Google Scholar 

  119. Zaulyanov L, Kirsner RS. A review of a bi-layered living cell treatment (Apligraf) in the treatment of venous leg ulcers and diabetic foot ulcers. Clin Interv Aging. 2007;2(1):93–8.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Gerlach JC, Johnen C, Ottomann C, Bräutigam K, Plettig J, Belfekroun C, et al. Method for autologous single skin cell isolation for regenerative cell spray transplantation with non-cultured cells. Int J Artificial Organs. 2011;34(3):271–9.

    Article  Google Scholar 

  121. Peirce SC, Carolan-Rees G. ReCell(®) spray-on skin system for treating skin loss, scarring and depigmentation after burn injury: a NICE medical technology guidance. Appl Health Econ Health Policy. 2019;17(2):131–41.

    Article  PubMed  Google Scholar 

  122. Ng WL, Wang S, Yeong WY, Naing MW. Skin bioprinting: impending reality or fantasy? Trends Biotechnol. 2016;34(9):689–99.

    Article  CAS  PubMed  Google Scholar 

  123. Pereira RF, Barrias CC, Granja PL, Bartolo PJ. Advanced biofabrication strategies for skin regeneration and repair. Nanomedicine (London, England). 2013;8(4):603–21.

    Article  CAS  Google Scholar 

  124. Guenou H, Nissan X, Larcher F, Feteira J, Lemaitre G, Saidani M, et al. Human embryonic stem-cell derivatives for full reconstruction of the pluristratified epidermis: a preclinical study. Lancet (London, England). 2009;374(9703):1745–53.

    Article  CAS  Google Scholar 

  125. Shamis Y, Hewitt KJ, Carlson MW, Margvelashvilli M, Dong S, Kuo CK, et al. Fibroblasts derived from human embryonic stem cells direct development and repair of 3D human skin equivalents. Stem Cell Res Ther. 2011;2(1):10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Tang KC, Yang KC, Lin CW, Chen YK, Lu TY, Chen HY, et al. Human adipose-derived stem cell secreted extracellular matrix incorporated into electrospun Poly(Lactic-co-Glycolic Acid) nanofibrous dressing for enhancing wound healing. Polymers. 2019;11(10).

    Google Scholar 

  127. Petry L, Kippenberger S, Meissner M, Kleemann J, Kaufmann R, Rieger UM, et al. Directing adipose-derived stem cells into keratinocyte-like cells: impact of medium composition and culture condition. J Eur Acad Dermatol Venereol JEADV. 2018;32(11):2010–9.

    Article  CAS  PubMed  Google Scholar 

  128. Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D, Shimizu H. Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol (Baltimore, Md: 1950). 2008;180(4):2581–7.

    Article  CAS  Google Scholar 

  129. Luo H, Guo Y, Liu Y, Wang Y, Zheng R, Ban Y, et al. Growth differentiation factor 11 inhibits adipogenic differentiation by activating TGF-beta/Smad signalling pathway. Cell Prolif. 2019;52(4):e12631.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Hanft JR, Surprenant MS. Healing of chronic foot ulcers in diabetic patients treated with a human fibroblast-derived dermis. J Foot Ankle Surg. 2002;41(5):291–9.

    Article  PubMed  Google Scholar 

  131. Itoh M, Umegaki-Arao N, Guo Z, Liu L, Higgins CA, Christiano AM. Generation of 3D skin equivalents fully reconstituted from human induced pluripotent stem cells (iPSCs). PLoS One. 2013;8(10):e77673-e.

    Article  CAS  Google Scholar 

  132. Fang H, Huang L, Welch I, Norley C, Holdsworth DW, Beier F, et al. Early changes of articular cartilage and subchondral bone in the DMM mouse model of osteoarthritis. Sci Rep. 2018;8(1):2855.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Cross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, et al. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014;73(7):1323–30.

    Article  PubMed  Google Scholar 

  134. McAlindon TE, LaValley MP, Harvey WF, Price LL, Driban JB, Zhang M, et al. Effect of Intra-articular Triamcinolone vs Saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial. JAMA. 2017;317(19):1967–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Montañez-Heredia E, Irízar S, Huertas PJ, Otero E, Del Valle M, Prat I, et al. Intra-articular injections of platelet-rich plasma versus hyaluronic acid in the treatment of osteoarthritic knee pain: a randomized clinical trial in the context of the Spanish National Health Care System. Int J Mol Sci. 2016;17(7)

    Google Scholar 

  136. Estades-Rubio FJ, Reyes-Martín A, Morales-Marcos V, García-Piriz M, García-Vera JJ, Perán M, et al. Knee viscosupplementation: cost-effectiveness analysis between stabilized hyaluronic acid in a single injection versus five injections of standard hyaluronic acid. Int J Mol Sci. 2017;18(3)

    Google Scholar 

  137. Gallagher B, Tjoumakaris FP, Harwood MI, Good RP, Ciccotti MG, Freedman KB. Chondroprotection and the prevention of osteoarthritis progression of the knee: a systematic review of treatment agents. Am J Sports Med. 2015;43(3):734–44.

    Article  PubMed  Google Scholar 

  138. Orth P, Gao L, Madry H. Microfracture for cartilage repair in the knee: a systematic review of the contemporary literature. Knee Surg Sports Traumatol Arthrosc. 2020;28(3):670–706.

    Article  PubMed  Google Scholar 

  139. Broyles JE, O'Brien MA, Stagg MP. Microdrilling surgery augmented with intra-articular bone marrow aspirate concentrate, platelet-rich plasma, and hyaluronic acid: a technique for cartilage repair in the knee. Arthrosc Tech. 2017;6(1):e201–e6.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Sanna M, Sanna C, Caputo F, Piu G, Salvi M. Surgical approaches in total knee arthroplasty. Joints. 2013;1(2):34–44.

    PubMed  PubMed Central  Google Scholar 

  141. Karataglis D, Green MA, Learmonth DJ. Autologous osteochondral transplantation for the treatment of chondral defects of the knee. Knee. 2006;13(1):32–5.

    Article  CAS  PubMed  Google Scholar 

  142. Kizaki K, El-Khechen HA, Yamashita F, Duong A, Simunovic N, Musahl V, et al. Arthroscopic versus open osteochondral autograft transplantation (Mosaicplasty) for cartilage damage of the knee: a systematic review. J Knee Surg. 2019.

    Google Scholar 

  143. Angermann P, Riegels-Nielsen P, Pedersen H. Osteochondritis dissecans of the femoral condyle treated with periosteal transplantation. Poor outcome in 14 patients followed for 6-9 years. Acta Orthop Scand. 1998;69(6):595–7.

    Article  CAS  PubMed  Google Scholar 

  144. Negoro T, Takagaki Y, Okura H, Matsuyama A. Trends in clinical trials for articular cartilage repair by cell therapy. NPJ Regen Med. 2018;3:17.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med. 1994;331(14):889–95.

    Article  CAS  PubMed  Google Scholar 

  146. Fickert S, Schattenberg T, Niks M, Weiss C, Thier S. Feasibility of arthroscopic 3-dimensional, purely autologous chondrocyte transplantation for chondral defects of the hip: a case series. Arch Orthop Trauma Surg. 2014;134(7):971–8.

    Article  CAS  PubMed  Google Scholar 

  147. Davies RL, Kuiper NJ. Regenerative medicine: a review of the evolution of autologous chondrocyte implantation (ACI) therapy. Bioengineering (Basel). 2019;6(1):22.

    Article  CAS  Google Scholar 

  148. Estes BT, Wu AW, Guilak F. Potent induction of chondrocytic differentiation of human adipose-derived adult stem cells by bone morphogenetic protein 6. Arthritis Rheum. 2006;54(4):1222–32.

    Article  CAS  PubMed  Google Scholar 

  149. Narakornsak S, Poovachiranon N, Peerapapong L, Pothacharoen P, Aungsuchawan S. Mesenchymal stem cells differentiated into chondrocyte-Like cells. Acta Histochem. 2016;118(4):418–29.

    Article  CAS  PubMed  Google Scholar 

  150. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105(4):1815–22.

    Article  CAS  PubMed  Google Scholar 

  151. Wakitani S, Mitsuoka T, Nakamura N, Toritsuka Y, Nakamura Y, Horibe S. Autologous bone marrow stromal cell transplantation for repair of full-thickness articular cartilage defects in human patellae: two case reports. Cell Transplant. 2004;13(5):595–600.

    Article  PubMed  Google Scholar 

  152. Matas J, Orrego M, Amenabar D, Infante C, Tapia-Limonchi R, Cadiz MI, et al. Umbilical cord-derived mesenchymal stromal cells (MSCs) for knee osteoarthritis: repeated MSC dosing is superior to a single MSC dose and to hyaluronic acid in a controlled randomized Phase I/II trial. Stem Cells Transl Med. 2019;8(3):215–24.

    Article  CAS  PubMed  Google Scholar 

  153. Castellanos R, Tighe S. Injectable amniotic membrane/umbilical cord particulate for knee osteoarthritis: a prospective, single-center pilot study. Pain Med. 2019;20(11):2283–91.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Khalifeh Soltani S, Forogh B, Ahmadbeigi N, Hadizadeh Kharazi H, Fallahzadeh K, Kashani L, et al. Safety and efficacy of allogenic placental mesenchymal stem cells for treating knee osteoarthritis: a pilot study. Cytotherapy. 2019;21(1):54–63.

    Article  PubMed  Google Scholar 

  155. González PL, Carvajal C, Cuenca J, Alcayaga-Miranda F, Figueroa FE, Bartolucci J, et al. Chorion mesenchymal stem cells show superior differentiation, immunosuppressive, and angiogenic potentials in comparison with haploidentical maternal placental cells. Stem Cells Transl Med. 2015;4(10):1109–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Organization WH. Classification of diabetes mellitus. 2019.

    Google Scholar 

  157. Farooq T, Rehman K, Hameed A, Akash MSH. Stem cell therapy and type 1 diabetes mellitus: treatment strategies and future perspectives. Tissue Eng Regen Med. 2019: Springer.

    Google Scholar 

  158. Alicka M, Marycz K. The effect of chronic inflammation and oxidative and endoplasmic reticulum stress in the course of metabolic syndrome and its therapy. Stem Cells Int. 2018;2018:4274361.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Cersosimo E, Triplitt C, Solis-Herrera C, Mandarino LJ, DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Endotext [Internet]: MDText. com, Inc.; 2018.

    Google Scholar 

  160. Mahmoud M, Abu-Shahba N, Azmy O, El-Badri N. Impact of diabetes mellitus on human mesenchymal stromal cell biology and functionality: implications for autologous transplantation. Stem Cell Rev Rep. 2019;15(2):194–217.

    Article  PubMed  Google Scholar 

  161. Mahaffey KW, Jardine MJ, Bompoint S, Cannon CP, Neal B, Heerspink HJ, et al. Canagliflozin and cardiovascular and renal outcomes in Type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups: results from the randomized CREDENCE trial. Circulation. 2019;140(9):739–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Braunwald E. Diabetes, heart failure, and renal dysfunction: the vicious circles. Prog Cardiovasc Dis. 2019;62(4):298–302.

    Article  PubMed  Google Scholar 

  163. Dunlay SM, Givertz MM, Aguilar D, Allen LA, Chan M, Desai AS, et al. Type 2 diabetes mellitus and heart failure: a scientific statement From the American Heart Association and the Heart Failure Society of America: this statement does not represent an update of the 2017 ACC/AHA/HFSA heart failure guideline update. Circulation. 2019;140(7):e294–324.

    Article  CAS  PubMed  Google Scholar 

  164. Han SB, Yang HK, Hyon JY. Influence of diabetes mellitus on anterior segment of the eye. Clin Interv Aging. 2019;14:53.

    Article  CAS  PubMed  Google Scholar 

  165. Huang X, Zhang P, Zou X, Xu Y, Zhu J, He J, et al. Two-year incidence and associated factors of dry eye among residents in Shanghai communities with type 2 diabetes mellitus. Eye Contact Lens. 2020;46:S42–S9.

    Article  PubMed  Google Scholar 

  166. Xiao Y, Chen M-J, Shen X, Lin L-R, Liu L-L, Yang T-C, et al. Metabolic disorders in patients with central nervous system infections: associations with neurosyphilis. Eur Neurol. 2019;81(5-6):270–7.

    Article  CAS  PubMed  Google Scholar 

  167. Ewers B, Trolle E, Jacobsen SS, Vististen D, Almdal TP, Vilsbøll T, et al. Dietary habits and adherence to dietary recommendations in patients with type 1 and type 2 diabetes compared with the general population in Denmark. Nutrition. 2019;61:49–55.

    Article  PubMed  Google Scholar 

  168. Montvida O, Green J, Atherton J, Paul S. Treatment with incretins does not increase the risk of pancreatic diseases compared to older anti-hyperglycaemic drugs, when added to metformin: real world evidence in people with Type 2 diabetes. Diabet Med. 2019;36(4):491–8.

    Article  CAS  PubMed  Google Scholar 

  169. Chong S, Ding D, Byun R, Comino E, Bauman A, Jalaludin B. Lifestyle changes after a diagnosis of type 2 diabetes. Diabetes Spectr. 2017;30(1):43–50.

    Google Scholar 

  170. Fanelli CG, Porcellati F, Pampanelli S, Bolli GB. Insulin therapy and hypoglycaemia: the size of the problem. Diabetes Metab Res Rev. 2004;20(S2):S32–42.

    Article  CAS  PubMed  Google Scholar 

  171. Street CN, Lakey JR, Shapiro AM, Imes S, Rajotte RV, Ryan EA, et al. Islet graft assessment in the Edmonton protocol: implications for predicting long-term clinical outcome. Diabetes. 2004;53(12):3107–14.

    Article  CAS  PubMed  Google Scholar 

  172. Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006;355(13):1318–30.

    Article  CAS  PubMed  Google Scholar 

  173. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000;343(4):230–8.

    Article  CAS  PubMed  Google Scholar 

  174. Maffi P, Secchi A. Islet transplantation alone versus solitary pancreas transplantation: an outcome-driven choice? Curr Diab Rep. 2019;19(5):26.

    Article  PubMed  Google Scholar 

  175. Oberholzer J, Triponez F, Mage R, Andereggen E, Bühler L, Crétin N, et al. Human islet transplantation: lessons from 13 autologous and 13 allogeneic transplantations. Transplantation. 2000;69(6):1115–23.

    Article  CAS  PubMed  Google Scholar 

  176. Chang CA, Lawrence MC, Naziruddin B. Current issues in allogeneic islet transplantation. Curr Opin Organ Transplant. 2017;22(5):437–43.

    Article  CAS  PubMed  Google Scholar 

  177. Badet L, Benhamou PY, Wojtusciszyn A, Baertschiger R, Milliat-Guittard L, Kessler L, et al. Expectations and strategies regarding islet transplantation: metabolic data from the GRAGIL 2 trial. Transplantation. 2007;84(1):89–96.

    Article  CAS  PubMed  Google Scholar 

  178. Pavathuparambil Abdul Manaph N, Sivanathan KN, Nitschke J, Zhou X-F, Coates PT, Drogemuller CJ. An overview on small molecule-induced differentiation of mesenchymal stem cells into beta cells for diabetic therapy. Stem Cell Res Ther. 2019;10(1):293.

    Article  PubMed  PubMed Central  Google Scholar 

  179. Mitutsova V, Yeo WWY, Davaze R, Franckhauser C, Hani E-H, Abdullah S, et al. Adult muscle-derived stem cells engraft and differentiate into insulin-expressing cells in pancreatic islets of diabetic mice. Stem Cell Res Ther. 2017;8(1):86.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  180. Kieffer TJ. Closing in on mass production of mature human beta cells. Cell Stem Cell. 2016;18(6):699–702.

    Article  CAS  PubMed  Google Scholar 

  181. El-Badri N, Ghoneim MA. Mesenchymal stem cell therapy in diabetes mellitus: progress and challenges. J Nucleic Acids. 2013;2013:194858.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Ardestani A, Maedler K. MST1: a promising therapeutic target to restore functional beta cell mass in diabetes. Diabetologia. 2016;59(9):1843–9.

    Article  CAS  PubMed  Google Scholar 

  183. Balaji S, Keswani SG, Crombleholme TM. The role of mesenchymal stem cells in the regenerative wound healing phenotype. Adv Wound Care (New Rochelle). 2012;1(4):159–65.

    Article  Google Scholar 

  184. Pagliuca FW, Millman JR, Gürtler M, Segel M, Van Dervort A, Ryu JH, et al. Generation of functional human pancreatic β cells in vitro. Cell. 2014;159(2):428–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Candiello J, Grandhi TSP, Goh SK, Vaidya V, Lemmon-Kishi M, Eliato KR, et al. 3D heterogeneous islet organoid generation from human embryonic stem cells using a novel engineered hydrogel platform. Biomaterials. 2018;177:27–39.

    Article  CAS  PubMed  Google Scholar 

  186. Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol. 2008;26(4):443–52.

    Article  CAS  PubMed  Google Scholar 

  187. Taneera J, Rosengren A, Renstrom E, Nygren JM, Serup P, Rorsman P, et al. Failure of transplanted bone marrow cells to adopt a pancreatic beta-cell fate. Diabetes. 2006;55(2):290–6.

    Article  CAS  PubMed  Google Scholar 

  188. Okura H, Komoda H, Fumimoto Y, Lee CM, Nishida T, Sawa Y, et al. Transdifferentiation of human adipose tissue-derived stromal cells into insulin-producing clusters. Journal of Artificial Organs. 2009;12(2):123–30.

    Article  CAS  PubMed  Google Scholar 

  189. Timper K, Seboek D, Eberhardt M, Linscheid P, Christ-Crain M, Keller U, et al. Human adipose tissue-derived mesenchymal stem cells differentiate into insulin, somatostatin, and glucagon expressing cells. Biochem Biophys Res Commun. 2006;341(4):1135–40.

    Article  CAS  PubMed  Google Scholar 

  190. Zhao Y, Jiang Z, Zhao T, Ye M, Hu C, Yin Z, et al. Reversal of type 1 diabetes via islet β cell regeneration following immune modulation by cord blood-derived multipotent stem cells. BMC Med. 2012;10:3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Negi N, Griffin MD. Effects of mesenchymal stromal cells on regulatory T cells: current understanding and clinical relevance. Stem Cells. 2020;38(5):596–605.

    Article  PubMed  PubMed Central  Google Scholar 

  192. Qi Y, Ma J, Li S, Liu W. Applicability of adipose-derived mesenchymal stem cells in treatment of patients with type 2 diabetes. Stem Cell Res Ther. 2019;10(1):274.

    Article  PubMed  PubMed Central  Google Scholar 

  193. Zang L, Hao H, Liu J, Li Y, Han W, Mu Y. Mesenchymal stem cell therapy in type 2 diabetes mellitus. Diabetol Metab Syndr. 2017;9:36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Bhansali S, Dutta P, Yadav MK, Jain A, Mudaliar S, Hawkins M, et al. Autologous bone marrow-derived mononuclear cells transplantation in type 2 diabetes mellitus: effect on β-cell function and insulin sensitivity. Diabetol Metab Syndr. 2017;9:50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Carlsson PO, Schwarcz E, Korsgren O, Le Blanc K. Preserved β-cell function in type 1 diabetes by mesenchymal stromal cells. Diabetes. 2015;64(2):587–92.

    Article  CAS  PubMed  Google Scholar 

  196. Bhansali A, Asokumar P, Walia R, Bhansali S, Gupta V, Jain A, et al. Efficacy and safety of autologous bone marrow-derived stem cell transplantation in patients with type 2 diabetes mellitus: a randomized placebo-controlled study. Cell Transplant. 2014;23(9):1075–85.

    Article  PubMed  Google Scholar 

  197. El-Badawy A, El-Badri N. Clinical efficacy of stem cell therapy for diabetes mellitus: a meta-analysis. PLoS One. 2016;11(4):e0151938.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Cheng SK, Park EY, Pehar A, Rooney AC, Gallicano GI. Current progress of human trials using stem cell therapy as a treatment for diabetes mellitus. Am J Stem Cells. 2016;5(3):74–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Prat A, Antel J. Pathogenesis of multiple sclerosis. Curr Opin Neurol. 2005;18(3):225–30.

    Article  CAS  PubMed  Google Scholar 

  200. Siotto M, Filippi MM, Simonelli I, Landi D, Ghazaryan A, Vollaro S, et al. Oxidative stress related to iron metabolism in relapsing remitting multiple sclerosis patients with low disability. Front Neurosci. 2019;13:86.

    Article  PubMed  PubMed Central  Google Scholar 

  201. Padureanu R, Albu CV, Mititelu RR, Bacanoiu MV, Docea AO, Calina D, et al. Oxidative stress and inflammation interdependence in multiple sclerosis. J Clin Med. 2019;8(11):1815.

    Article  CAS  PubMed Central  Google Scholar 

  202. Klotz L, Havla J, Schwab N, Hohlfeld R, Barnett M, Reddel S, et al. Risks and risk management in modern multiple sclerosis immunotherapeutic treatment. Ther Adv Neurol Disord. 2019;12:1756286419836571.

    Article  PubMed  PubMed Central  Google Scholar 

  203. Swart JF, Delemarre EM, van Wijk F, Boelens J-J, Kuball J, van Laar JM, et al. Haematopoietic stem cell transplantation for autoimmune diseases. Nat Rev Rheumatol. 2017;13(4):244–56.

    Article  CAS  PubMed  Google Scholar 

  204. Lowenthal RM, Cohen ML, Atkinson K, Biggs JC. Apparent cure of rheumatoid arthritis by bone marrow transplantation. J Rheumatol. 1993;20(1):137–40.

    CAS  PubMed  Google Scholar 

  205. Weissman IL, Shizuru JA. The origins of the identification and isolation of hematopoietic stem cells, and their capability to induce donor-specific transplantation tolerance and treat autoimmune diseases. Blood. 2008;112(9):3543–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Fassas AS, Passweg JR, Anagnostopoulos A, Kazis A, Kozak T, Havrdova E, et al. Hematopoietic stem cell transplantation for multiple sclerosis. J Neurol. 2002;249(8):1088–97.

    Article  CAS  PubMed  Google Scholar 

  207. Burt RK, Traynor AE, Cohen B, Karlin KH, Davis FA, Stefoski D, et al. T cell-depleted autologous hematopoietic stem cell transplantation for multiple sclerosis: report on the first three patients. Bone Marrow Transplant. 1998;21(6):537–41.

    Article  CAS  PubMed  Google Scholar 

  208. Saccardi R, Tyndall A, Coghlan G, Denton C, Edan G, Emdin M, et al. Consensus statement concerning cardiotoxicity occurring during haematopoietic stem cell transplantation in the treatment of autoimmune diseases, with special reference to systemic sclerosis and multiple sclerosis. Bone Marrow Transplant. 2004;34(10):877–81.

    Article  CAS  PubMed  Google Scholar 

  209. Daikeler T, Tichelli A, Passweg J. Complications of autologous hematopoietic stem cell transplantation for patients with autoimmune diseases. Pediatr Res. 2012. https://doi.org/10.1038/pr.2011.57

  210. Gharibi T, Ahmadi M, Seyfizadeh N, Jadidi-Niaragh F, Yousefi M. Immunomodulatory characteristics of mesenchymal stem cells and their role in the treatment of Multiple Sclerosis. Cell Immunol. 2015;293(2):113–21.

    Article  CAS  PubMed  Google Scholar 

  211. Le Blanc K, Ringdén O. Immunomodulation by mesenchymal stem cells and clinical experience. J Intern Med. 2007;262(5):509–25.

    Article  PubMed  CAS  Google Scholar 

  212. Dahbour S, Jamali F, Alhattab D, Al-Radaideh A, Ababneh O, Al-Ryalat N, et al. Mesenchymal stem cells and conditioned media in the treatment of multiple sclerosis patients: Clinical, ophthalmological and radiological assessments of safety and efficacy. CNS Neurosci Ther. 2017;23(11):866–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Cohen JA. Mesenchymal stem cell transplantation in multiple sclerosis. J Neurol Sci. 2013;333(1):43–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Riordan NH, Morales I, Fernández G, Allen N, Fearnot NE, Leckrone ME, et al. Clinical feasibility of umbilical cord tissue-derived mesenchymal stem cells in the treatment of multiple sclerosis. J Transl Med. 2018;16(1):57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Pringsheim T, Jette N, Frolkis A, Steeves TDL. The prevalence of Parkinson’s disease: a systematic review and meta-analysis. Mov Disord. 2014;29(13):1583–90.

    Article  PubMed  Google Scholar 

  216. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol. 1999;56(1):33–9.

    Article  CAS  PubMed  Google Scholar 

  217. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276(5321):2045–7.

    Article  CAS  PubMed  Google Scholar 

  218. Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, et al. [Alpha]-synuclein locus triplication causes Parkinson’s disease. Science. 2003;302:841.

    Article  CAS  PubMed  Google Scholar 

  219. Jankovic J. Complications and limitations of drug therapy for Parkinson’s disease. Neurology. 2000;55(12 Suppl 6):S2–6.

    CAS  PubMed  Google Scholar 

  220. Stocchi F, Tagliati M, Olanow CW. Treatment of levodopa-induced motor complications. Mov Disord. 2008;23(S3):S599–612.

    Article  PubMed  Google Scholar 

  221. Jiang H, Ren Y, Yuen EY, Zhong P, Ghaedi M, Hu Z, et al. Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells. Nat Commun. 2012;3(1):668.

    Article  PubMed  CAS  Google Scholar 

  222. Schulz TC, Noggle SA, Palmarini GM, Weiler DA, Lyons IG, Pensa KA, et al. Differentiation of human embryonic stem cells to dopaminergic neurons in serum-free suspension culture. Stem Cells. 2004;22(7):1218–38.

    Article  CAS  PubMed  Google Scholar 

  223. Swistowski A, Peng J, Liu Q, Mali P, Rao MS, Cheng L, et al. Efficient generation of functional dopaminergic neurons from human induced pluripotent stem cells under defined conditions. Stem Cells. 2010;28(10):1893–904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Brederlau A, Correia AS, Anisimov SV, Elmi M, Paul G, Roybon L, et al. Transplantation of human embryonic stem cell-derived cells to a rat model of Parkinson's disease: effect of in vitro differentiation on graft survival and Teratoma formation. Stem Cells. 2006;24(6):1433–40.

    Article  CAS  PubMed  Google Scholar 

  225. Wang Y-K, Zhu W-W, Wu M-H, Wu Y-H, Liu Z-X, Liang L-M, et al. Human clinical-grade parthenogenetic ESC-derived dopaminergic neurons recover locomotive defects of nonhuman primate models of Parkinson’s disease. Stem Cell Reports. 2018;11(1):171–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Mahajani S, Raina A, Fokken C, Kügler S, Bähr M. Homogenous generation of dopaminergic neurons from multiple hiPSC lines by transient expression of transcription factors. Cell Death Dis. 2019;10(12):898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Schweitzer JS, Song B, Herrington TM, Park T-Y, Lee N, Ko S, et al. Personalized iPSC-derived dopamine progenitor cells for Parkinson’s disease. N Engl J Med. 2020;382(20):1926–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Kang EJ, Lee YH, Kim MJ, Lee YM, Kumar BM, Jeon BG, et al. Transplantation of porcine umbilical cord matrix mesenchymal stem cells in a mouse model of Parkinson’s disease. J Tissue Eng Regen Med. 2013;7(3):169–82.

    Article  CAS  PubMed  Google Scholar 

  229. Park H-J, Shin JY, Lee BR, Kim HO, Lee PH. Mesenchymal stem cells augment neurogenesis in the subventricular zone and enhance differentiation of neural precursor cells into dopaminergic neurons in the Substantia Nigra of a Parkinsonian model. Cell Transplant. 2012;21(8):1629–40.

    Article  PubMed  Google Scholar 

  230. Park HJ, Shin JY, Kim HN, Oh SH, Lee PH. Neuroprotective effects of mesenchymal stem cells through autophagy modulation in a parkinsonian model. Neurobiol Aging. 2014;35(8):1920–8.

    Article  CAS  PubMed  Google Scholar 

  231. Chen H-X, Liang F-C, Gu P, Xu B-L, Xu H-J, Wang W-T, et al. Exosomes derived from mesenchymal stem cells repair a Parkinson’s disease model by inducing autophagy. Cell Death Dis. 2020;11(4):288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Vilaça-Faria H, Salgado AJ, Teixeira FG. Mesenchymal stem cells-derived exosomes: a new possible therapeutic strategy for Parkinson’s disease? Cell. 2019;8(2).

    Google Scholar 

  233. Teixeira FG, Carvalho MM, Panchalingam KM, Rodrigues AJ, Mendes-Pinheiro B, Anjo S, et al. Impact of the secretome of human mesenchymal stem cells on brain structure and animal behavior in a rat model of Parkinson’s disease. Stem Cells Transl Med. 2017;6(2):634–46.

    Article  CAS  PubMed  Google Scholar 

  234. Venkataramana NK, Kumar SKV, Balaraju S, Radhakrishnan RC, Bansal A, Dixit A, et al. Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson’s disease. Transl Res. 2010;155(2):62–70.

    Article  CAS  PubMed  Google Scholar 

  235. Liu X-S, Li J-F, Wang S-S, Wang Y-T, Zhang Y-Z, Yin H-L, et al. Human umbilical cord mesenchymal stem cells infected with adenovirus expressing <i>HGF</i> promote regeneration of damaged neuron cells in a Parkinson’s Disease Model. Biomed Res Int. 2014;2014:909657.

    PubMed  PubMed Central  Google Scholar 

  236. Yan M, Sun M, Zhou Y, Wang W, He Z, Tang D, et al. Conversion of human umbilical cord mesenchymal stem cells in Wharton’s Jelly to Dopamine Neurons Mediated by the Lmx1a and Neurturin In Vitro: Potential Therapeutic Application for Parkinson’s Disease in a Rhesus Monkey Model. PLoS One. 2013;8(5):e64000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Shetty P, Ravindran G, Sarang S, Thakur AM, Rao HS, Viswanathan C. Clinical grade mesenchymal stem cells transdifferentiated under xenofree conditions alleviates motor deficiencies in a rat model of Parkinson’s disease. Cell Biol Int. 2009;33(8):830–8.

    Article  CAS  PubMed  Google Scholar 

  238. Bjugstad KB, Teng YD, Redmond DE, Elsworth JD, Roth RH, Cornelius SK, et al. Human neural stem cells migrate along the nigrostriatal pathway in a primate model of Parkinson’s disease. Exp Neurol. 2008;211(2):362–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Nowak JZ. Age-related macular degeneration (AMD): pathogenesis and therapy. Pharmacol Rep. 2006;58(3):353.

    CAS  PubMed  Google Scholar 

  240. Ambati J, Ambati BK, Yoo SH, Ianchulev S, Adamis AP. Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies. Surv Ophthalmol. 2003;48(3):257–93.

    Article  PubMed  Google Scholar 

  241. Storchi R, Rodgers J, Gracey M, Martial FP, Wynne J, Ryan S, et al. Measuring vision using innate behaviours in mice with intact and impaired retina function. Sci Rep. 2019;9(1):1–16.

    Article  CAS  Google Scholar 

  242. Procyk CA, Eleftheriou CG, Storchi R, Allen AE, Milosavljevic N, Brown TM, et al. Spatial receptive fields in the retina and dorsal lateral geniculate nucleus of mice lacking rods and cones. J Neurophysiol. 2015;114(2):1321–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Swanson MW, McGwin G Jr. Anti-inflammatory drug use and age-related macular degeneration. Optom Vis Sci. 2008;85(10):947–50.

    Article  PubMed  Google Scholar 

  244. Schmidt-Erfurth U, Hasan T. Mechanisms of action of photodynamic therapy with verteporfin for the treatment of age-related macular degeneration. Surv Ophthalmol. 2000;45(3):195–214.

    Article  CAS  PubMed  Google Scholar 

  245. Spaide RF, Laud K, Fine HF, James M, Klancnik J, Meyerle CB, Yannuzzi LA, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina. 2006;26(4):383–90.

    PubMed  Google Scholar 

  246. Martin DF, Maguire MG, Fine SL, G-s Y, Jaffe GJ, Grunwald JE, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388–98.

    Article  PubMed  Google Scholar 

  247. Li LX, Turner JE. Inherited retinal dystrophy in the RCS rat: prevention of photoreceptor degeneration by pigment epithelial cell transplantation. Exp Eye Res. 1988;47(6):911–7.

    Article  CAS  PubMed  Google Scholar 

  248. Klassen HJ, Ng TF, Kurimoto Y, Kirov I, Shatos M, Coffey P, et al. Multipotent retinal progenitors express developmental markers, differentiate into retinal neurons, and preserve light-mediated behavior. Invest Ophthalmol Vis Sci. 2004;45(11):4167–73.

    Article  PubMed  Google Scholar 

  249. Luo J, Baranov P, Patel S, Ouyang H, Quach J, Wu F, et al. Human retinal progenitor cell transplantation preserves vision. J Biol Chem. 2014;289(10):6362–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Lin B, McLelland BT, Mathur A, Aramant RB, Seiler MJ. Sheets of human retinal progenitor transplants improve vision in rats with severe retinal degeneration. Exp Eye Res. 2018;174:13–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Yanai A, Laver CR, Joe AW, Viringipurampeer IA, Wang X, Gregory-Evans CY, et al. Differentiation of human embryonic stem cells using size-controlled embryoid bodies and negative cell selection in the production of photoreceptor precursor cells. Tissue Eng Part C: Methods. 2013;19(10):755–64.

    Article  CAS  Google Scholar 

  252. Schwartz SD, Hubschman J-P, Heilwell G, Franco-Cardenas V, Pan CK, Ostrick RM, et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet. 2012;379(9817):713–20.

    Article  CAS  PubMed  Google Scholar 

  253. Chakradhar S. An eye to the future: researchers debate best path for stem cell–derived therapies. Nature Publishing Group; 2016.

    Google Scholar 

  254. Garber K. RIKEN suspends first clinical trial involving induced pluripotent stem cells. Nature Publishing Group; 2015.

    Google Scholar 

  255. Petrus-Reurer S, Kumar P, Padrell Sánchez S, Aronsson M, André H, Bartuma H, et al. Preclinical safety studies of human embryonic stem cell-derived retinal pigment epithelial cells for the treatment of age-related macular degeneration. Stem Cells Transl Med. 2020.

    Google Scholar 

  256. Capowski EE, Samimi K, Mayerl SJ, Phillips MJ, Pinilla I, Howden SE, et al. Reproducibility and staging of 3D human retinal organoids across multiple pluripotent stem cell lines. Development. 2019;146(1):dev171686.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  257. Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Morinaga C, Daimon T, et al. Autologous induced stem-cell–derived retinal cells for macular degeneration. N Engl J Med. 2017;376(11):1038–46.

    Article  CAS  PubMed  Google Scholar 

  258. Arnhold S, Absenger Y, Klein H, Addicks K, Schraermeyer U. Transplantation of bone marrow-derived mesenchymal stem cells rescue photoreceptor cells in the dystrophic retina of the rhodopsin knockout mouse. Graefe’s archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2007;245(3):414–22.

    Google Scholar 

  259. Kicic A, Shen WY, Wilson AS, Constable IJ, Robertson T, Rakoczy PE. Differentiation of marrow stromal cells into photoreceptors in the rat eye. J Neurosci. 2003;23(21):7742–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Saraf SS, Cunningham MA, Kuriyan AE, Read SP, Rosenfeld PJ, Flynn HW Jr, et al. Bilateral retinal detachments after intravitreal injection of adipose-derived ‘stem cells’ in a patient with exudative macular degeneration. Ophthalmic Surg Lasers Imaging Retina. 2017;48(9):772–5.

    Article  PubMed  Google Scholar 

  261. Pean CA, Kingery MT, Strauss E, Bosco JA, Halbrecht J. Direct-to-consumer advertising of stem cell clinics: ethical considerations and recommendations for the health-care community. J Bone Joint Surg Am. 2019;101(19):e103.

    Article  PubMed  Google Scholar 

  262. Turner L, The US. Direct-to-consumer marketplace for autologous stem cell interventions. Perspect Biol Med. 2018;61(1):7–24.

    Article  PubMed  Google Scholar 

  263. Turner L, Knoepfler P. Selling Stem cells in the USA: assessing the direct-to-consumer industry. Cell Stem Cell. 2016;19(2):154–7.

    Article  CAS  PubMed  Google Scholar 

  264. Snyder J, Turner L, Crooks VA. Crowdfunding for unproven stem cell–based interventions. JAMA. 2018;319(18):1935–6.

    Article  PubMed  PubMed Central  Google Scholar 

  265. Lysaght T, Munsie M, Hendl T, Tan L, Kerridge I, Stewart C. Selling stem cells with tokens of legitimacy: an analysis of websites in Japan and Australia. Cytotherapy. 2018;20(5):S77–S8.

    Article  Google Scholar 

  266. Lau D, Ogbogu U, Taylor B, Stafinski T, Menon D, Caulfield T. Stem cell clinics online: the direct-to-consumer portrayal of stem cell medicine. Cell Stem Cell. 2008;3(6):591–4.

    Article  CAS  PubMed  Google Scholar 

  267. Piuzzi NS, Dominici M, Long M, Pascual-Garrido C, Rodeo S, Huard J, et al. Proceedings of the signature series symposium “cellular therapies for orthopaedics and musculoskeletal disease proven and unproven therapies-promise, facts and fantasy,” international society for cellular therapies, Montreal, Canada, May 2, 2018. Cytotherapy. 2018;20(11):1381–400.

    Article  PubMed  PubMed Central  Google Scholar 

  268. Kuriyan AE, Albini TA, Townsend JH, Rodriguez M, Pandya HK, Leonard RE, et al. Vision loss after intravitreal injection of autologous “Stem Cells” for AMD. N Engl J Med. 2017;376(11):1047–53.

    Article  PubMed  PubMed Central  Google Scholar 

  269. Belmonte JCI, Ellis J, Hochedlinger K, Yamanaka S. Induced pluripotent stem cells and reprogramming: seeing the science through the hype. Nat Rev Genet. 2009;10(12):878–83.

    Article  CAS  Google Scholar 

  270. Petrini C. Umbilical cord blood collection, storage and use: ethical issues. Blood Transfus. 2010;8(3):139.

    PubMed  PubMed Central  Google Scholar 

  271. Stewart CL, Aparicio LC, Kerridge IH. Ethical and legal issues raised by cord blood banking - the challenges of the new bioeconomy. Med J Aust. 2013;199(4):290–2.

    Article  PubMed  Google Scholar 

  272. Dessels C, Alessandrini M, Pepper MS. Factors influencing the umbilical cord blood stem cell industry: an evolving treatment landscape. Stem Cells Transl Med. 2018;7(9):643–50.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by grant # 5300 from the Egyptian Science and Technology Development Fund (STDF), and by internal funding from Zewail City of Science and Technology (ZC 003-2019).

Take Home Message

  • The biology of stem cells in tissue homeostasis and development has made it the prospect for the field of regenerative medicine.

  • Stem cell potency is more pronounced in embryonic tissues compared to adult cells. In the adult tissues, stem cells are widely distributed throughout the body including, but not limited to, the bone marrow, adipose tissue, intestine, skin, synovial membrane, and dental pulp.

  • Reprogramming somatic cells by induced pluripotent stem cell (iPSC) technology, gene editing, and applying modern techniques of nanotechnology and bioprinting have all made it possible for extensive applications of adult stem cells in regenerative medicine.

  • Hematopoietic stem cells transplantation (HSCT) is already a routine practice, and has secured FDA approval for its cellular products to treat hematological diseases.

  • Research is still in progress for wound healing and osteoarthritis treatment using stem cells.

  • Preclinical and clinical studies showed new hope in treating incurable chronic diseases like multiple sclerosis, macular degeneration, Parkinson’s Disease, and diabetes mellitus with stem cells.

  • FDA, CDC, ISSCR and other stem cell societies and institutes are regularly warning about the misused stem cell therapy away from their approved applications to minimize patients’ risks.

  • Various types of stem cells need more clinical investigations to test their safety and efficacy before being clinically translated.

  • Patients have to be cautious about the credibility of any cell-based medical application; and especially before undergoing stem cell therapy.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nagwa El-Badri .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Essawy, M., Shouman, S., Magdy, S., Abdelfattah-Hassan, A., El-Badri, N. (2020). Introduction and Basic Concepts in Stem Cell Research and Therapy: The Facts and the Hype. In: El-Badri, N. (eds) Regenerative Medicine and Stem Cell Biology . Learning Materials in Biosciences. Springer, Cham. https://doi.org/10.1007/978-3-030-55359-3_1

Download citation

Publish with us

Policies and ethics