Advertisement

MSC Therapy of Inborn Errors

  • Edwin M. Horwitz
Chapter
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)

Abstract

Mesenchymal stromal cells are ideally suited as cell therapy for inborn errors. While there are several potential mechanisms of therapeutic activity, in all studies yet, MSCs seem to exert their effects through the release of soluble mediators. This vast secretome, together with the capacity to modulate gene expression of the MSC therapeutic product through optimal selection of tissue source and ex vivo expansion protocols, suggests the potential to develop broadly applicable therapy for a wide array of disorders. However, the clinical experience to date is limited, most likely due to our unrealized historic view that MSCs were stem cells that could regenerate tissue. A pilot study in children with metachromatic leukodystrophy showed that MSCs may be able to increase nerve conduction velocity, suggesting that the cells may be stimulating remyelination of peripheral nerves. In osteogenesis imperfecta, MSCs unambiguously stimulate growth of the children who exhibit the characteristic severe growth deficiency. As our understanding of the fundamental biology of MSCs continues to improve, enthusiasm to assess MSCs in patients with inborn errors is also growing. The coming decade promises a swell of clinical trials and likely important breakthroughs.

Keywords

Bone Marrow Transplantation Mesenchymal Cell Osteogenesis Imperfecta Mesenchymal Stromal Cell Inborn Error 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Pittenger MF, Mackay AM, Beck SC et al (1999) Multilineage potential of adult human ­mesenchymal stem cells. Science 284:143–147PubMedCrossRefGoogle Scholar
  2. 2.
    Horwitz E, LeBlanc K, Dominici M et al (2005) Clarification of the nomenclature for MSC: the International Society for Cellular Therapy position statement. Cytotherapy 7:393–395PubMedCrossRefGoogle Scholar
  3. 3.
    Pereira RF, O’Hara MD, Laptev AV et al (1998) Marrow stromal cells as a source of progenitor cells for nonhematopoietic tissues in transgenic mice with a phenotype of osteogenesis imperfecta. Proc Natl Acad Sci USA 95:1142–1147PubMedCrossRefGoogle Scholar
  4. 4.
    Caplan AI (1991) Mesenchymal stem cells. J Orthop Res 9:641–650PubMedCrossRefGoogle Scholar
  5. 5.
    Caplan AI, Bruder SP (2001) Mesenchymal stem cells: building blocks for molecular medicine in the 21st century. Trends Mol Med 7:259–264PubMedCrossRefGoogle Scholar
  6. 6.
    Prockop DJ (1997) Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276:71–74PubMedCrossRefGoogle Scholar
  7. 7.
    Horwitz EM, Dominici M (2008) How do mesenchymal stromal cells exert their therapeutic benefit? Cytotherapy 10:771–774PubMedCrossRefGoogle Scholar
  8. 8.
    Phinney DG, Prockop DJ (2007) Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair–current views. Stem Cells 25:2896–2902PubMedCrossRefGoogle Scholar
  9. 9.
    Terada N, Hamazaki T, Oka M et al (2002) Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416:542–545PubMedCrossRefGoogle Scholar
  10. 10.
    Ying QL, Nichols J, Evans EP, Smith AG (2002) Changing potency by spontaneous fusion. Nature 416:545–548PubMedCrossRefGoogle Scholar
  11. 11.
    Spees JL, Olson SD, Ylostalo J et al (2003) Differentiation, cell fusion, and nuclear fusion during ex vivo repair of epithelium by human adult stem cells from bone marrow stroma. Proc Natl Acad Sci USA 100:2397–2402PubMedCrossRefGoogle Scholar
  12. 12.
    Olsen I, Muir H, Smith R, Fensom A, Watt DJ (1983) Direct enzyme transfer from lymphocytes is specific. Nature 306:75–77PubMedCrossRefGoogle Scholar
  13. 13.
    Abraham D, Muir H, Olsen I, Winchester B (1985) Direct enzyme transfer from lymphocytes corrects a lysosomal storage disease. Biochem Biophys Res Commun 129:417–425PubMedCrossRefGoogle Scholar
  14. 14.
    Walkley SU, Thrall MA, Dobrenis K et al (1994) Bone marrow transplantation corrects the enzyme defect in neurons of the central nervous system in a lysosomal storage disease. Proc Natl Acad Sci USA 91:2970–2974PubMedCrossRefGoogle Scholar
  15. 15.
    Will A, Cooper A, Hatton C, Sardharwalla IB, Evans DI, Stevens RF (1987) Bone marrow transplantation in the treatment of alpha-mannosidosis. Arch Dis Child 62:1044–1049PubMedCrossRefGoogle Scholar
  16. 16.
    Ponomaryov T, Peled A, Petit I et al (2000) Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function. J Clin Invest 106:1331–1339PubMedCrossRefGoogle Scholar
  17. 17.
    Peled A, Petit I, Kollet O et al (1999) Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 283:845–848PubMedCrossRefGoogle Scholar
  18. 18.
    Deans RJ, Moseley AB (2000) Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 28:875–884PubMedCrossRefGoogle Scholar
  19. 19.
    Majumdar MK, Thiede MA, Mosca JD, Moorman M, Gerson SL (1998) Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells. J Cell Physiol 176:57–66PubMedCrossRefGoogle Scholar
  20. 20.
    Honczarenko M, Le Y, Swierkowski M, Ghiran I, Glodek AM, Silberstein LE (2006) Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors. Stem Cells 24:1030–1041PubMedCrossRefGoogle Scholar
  21. 21.
    Muller I, Kustermann-Kuhn B, Holzwarth C et al (2006) In vitro analysis of multipotent mesenchymal stromal cells as potential cellular therapeutics in neurometabolic diseases in pediatric patients. Exp Hematol 34:1413–1419PubMedCrossRefGoogle Scholar
  22. 22.
    Di Nicola M, Carlo-Stella C, Magni M et al (2002) Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99:3838–3843PubMedCrossRefGoogle Scholar
  23. 23.
    Le Blanc K, Frassoni F, Ball L et al (2008) Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371:1579–1586PubMedCrossRefGoogle Scholar
  24. 24.
    Ren G, Zhang L, Zhao X et al (2008) Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2:141–150PubMedCrossRefGoogle Scholar
  25. 25.
    Francois M, Romieu-Mourez R, Li M, Galipeau J (2011) Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation. Mol Ther. doi: 10.1038/mt.2011.189
  26. 26.
    Nauta AJ, Westerhuis G, Kruisselbrink AB, Lurvink EG, Willemze R, Fibbe WE (2006) Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting. Blood 108:2114–2120PubMedCrossRefGoogle Scholar
  27. 27.
    Sudres M, Norol F, Trenado A et al (2006) Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice. J Immunol 176:7761–7767PubMedGoogle Scholar
  28. 28.
    Koc ON, Day J, Nieder M, Gerson SL, Lazarus HM, Krivit W (2002) Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Transplant 30:215–222PubMedCrossRefGoogle Scholar
  29. 29.
    Sillence DO (1997) Disorders of bone density, volume, and mineralization. In: Rimoin DL, Connor JM, Pyeritz RE (eds) Emery and Rimoin’s principles and practice of medical genetics, vol II, 3rd edn. Churchill Livingstone, New York, pp 2817–2835Google Scholar
  30. 30.
    Byers PH, Scriver CR, Beaudet AL, Sly WS, Valle D (1995) Disorders of collagen biosynthesis and structure. The metabolic and molecular bases of inherited disease, vol 7. McGraw-Hill, New York, pp 4029–4077Google Scholar
  31. 31.
    Horwitz EM, Prockop DJ, Fitzpatrick LA et al (1999) Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 5:309–313PubMedCrossRefGoogle Scholar
  32. 32.
    Horwitz EM, Prockop DJ, Gordon PL et al (2001) Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta. Blood 97:1227–1231PubMedCrossRefGoogle Scholar
  33. 33.
    Horwitz EM, Gordon PL, Koo WKK et al (2002) Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone. Proc Natl Acad Sci USA 99:8932–8937PubMedCrossRefGoogle Scholar
  34. 34.
    Hamill PV, Drizd TA, Johnson CL, Reed RB, Roche AF, Moore WM (1979) Physical growth: national center for health statistics percentiles. Am J Clin Nutr 32:607–629PubMedGoogle Scholar
  35. 35.
    Bartholomew A, Sturgeon C, Siatskas M et al (2002) Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 30:42–48PubMedCrossRefGoogle Scholar
  36. 36.
    Horwitz EM (2003) Stem cell plasticity: a new image of the bone marrow stem cell. Curr Opin Pediatr 15:32–37PubMedCrossRefGoogle Scholar
  37. 37.
    Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O (2003) Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 57:11–20PubMedCrossRefGoogle Scholar
  38. 38.
    Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R (1998) Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 339:947–952PubMedCrossRefGoogle Scholar
  39. 39.
    Roldan EJ, Pasqualini T, Plantalech L (1999) Bisphosphonates in children with osteogenesis imperfecta may improve bone mineralization but not bone strength. Report of two patients. J Pediatr Endocrinol Metab 12:555–559PubMedCrossRefGoogle Scholar
  40. 40.
    Mashiba T, Hirano T, Turner CH, Forwood MR, Johnston CC, Burr DB (2000) Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 15:613–620PubMedCrossRefGoogle Scholar
  41. 41.
    Daly K, Wisbeach A, Sanpera I, Fixsen JA (1996) The prognosis for walking in osteogenesis imperfecta. J Bone Joint Surg Br 78:477–480PubMedGoogle Scholar
  42. 42.
    Wilkinson JM, Scott BW, Bell MJ (1997) The prognosis for walking in osteogenesis ­imperfecta. J Bone Joint Surg Br 79:339PubMedCrossRefGoogle Scholar
  43. 43.
    Engelbert RH, Uiterwaal CS, Gulmans VA, Pruijs H, Helders PJ (2000) Osteogenesis imperfecta in childhood: prognosis for walking. J Pediatr 137:397–402PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Division of Oncology/Blood and Marrow Transplantation, The Children’s Hospital of PhiladelphiaThe University of Pennsylvania Perelman School of MedicinePhiladelphiaUSA

Personalised recommendations