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The Biology and Regenerative Potential of Stem Cells and Their Mesenchymal Progeny

  • Markus Neubauer
  • Heike Wegmeyer
  • Ralf Huss
Chapter
Part of the Stem Cells and Cancer Stem Cells book series (STEM, volume 6)

Abstract

Stem cells represent a promising novel therapeutic modality for the treatment of devastating diseases with high unmet medical need. Amongst the various types of stem cells, adult mesenchymal stromal cells (MSCs) emerged as cells with unique biological properties making them candidates for the treatment of autoimmune or inflammatory diseases or e.g. progressive organ failure. Here, the history of MSCs in the context of hematopoiesis and bone marrow transplantation, their in vivo origin in mesenchymal compartments, and their in vitro properties are highlighted. Proposed modes of action of MSCs and deduced potential targets of MSC therapy are discussed. Last but not least, an overview of the current status of cellular therapy approaches and future prospects is given regarding clinical testing of cells and future technological opportunities.

Keywords

Mesenchymal Stem Cell Acute Kidney Injury Mesenchymal Stromal Cell Graft Versus Host Disease Endogenous Repair 
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. Alison MR, Islam S, Lim SM (2009) Cell therapy for liver disease. Curr Opin Mol Ther 11:364–374PubMedGoogle Scholar
  2. Bianco P, Riminucci M, Kuznetsov S, Robey PG (2010) Multipotential cells in the bone marrow stroma: regulation in the context of organ physiology. Crit Rev Eukaryot Gene Expr 9:159–173Google Scholar
  3. Caplan AI (1991) Mesenchymal stem cells. J Orthop Res 9:641–650PubMedCrossRefGoogle Scholar
  4. Chang W, Song BW, Lim S, Song H, Shim CY, Cha MJ, Ahn DH, Jung YG, Lee DH, Chung JH, Choi KD, Lee SK, Chung N, Lee SK, Jang Y, Hwang KC (2009) Mesenchymal stem cells pretreated with delivered Hph-1-Hsp70 protein are protected from hypoxia-mediated cell death and rescue heart functions from myocardial injury. Stem Cells 27:2283–2292PubMedCrossRefGoogle Scholar
  5. Chen S, Liu Z, Tian N, Zhang J, Yei F, Duan B, Zhu Z, Lin S, Kwan TW (2006) Intracoronary transplantation of autologous bone marrow mesenchymal stem cells for ischemic cardiomyopathy due to isolated chronic occluded left anterior descending artery. J Invasive Cardiol 18:552–556PubMedGoogle Scholar
  6. Cheng Z, Ou L, Zhou X, Li F, Jia X, Zhang Y, Liu X, Li Y, Ward CA, Melo LG, Kong D (2008) Targeted migration of mesenchymal stem cells modified with CXCR4 gene to infarcted myocardium improves cardiac performance. Mol Ther 16:571–579PubMedCrossRefGoogle Scholar
  7. Cossu G, Bianco P (2003) Mesoangioblasts – vascular progenitors for extravascular mesodermal tissues. Curr Opin Genet Dev 13:537–542PubMedCrossRefGoogle Scholar
  8. Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, Andriolo G, Sun B, Zheng B, Zhang L, Norotte C, Teng PN, Traas J, Schugar R, Deasy BM, Badylak S, Buhring HJ, Giacobino JP, Lazzari L, Huard J, Peault B (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3:301–313PubMedCrossRefGoogle Scholar
  9. Crosby LM, Waters CM (2010) Epithelial repair mechanisms in the lung. Am J Physiol Lung Cell Mol Physiol 298:L715–L731PubMedCrossRefGoogle Scholar
  10. D’Ippolito G, D’Ippolito G, Diabira S, Diabira S, Howard GA, Howard GA, Menei P, Menei P, Roos BA, Roos BA, Schiller PC, Schiller PC (2004) Marrow-isolated adult multilineage inducible (MIAMI) cells, a unique population of postnatal young and old human cells with extensive expansion and differentiation potential. J Cell Sci 117:2971–2981PubMedCrossRefGoogle Scholar
  11. Dazzi F, Ramasamy R, Glennie S, Jones SP, Roberts I (2006) The role of mesenchymal stem cells in haemopoiesis. Blood Rev 20:161–171PubMedCrossRefGoogle Scholar
  12. Deng W, Chen QW, Li XS, Liu H, Niu SQ, Zhou Y, Li GQ, Ke DZ, Mo XG (2011) Bone marrow mesenchymal stromal cells with support of bispecific antibody and ultrasound-mediated microbubbles prevent myocardial fibrosis via the signal transducer and activators of transcription signaling pathway. Cytotherapy 13:431–440PubMedCrossRefGoogle Scholar
  13. Dennis JE, Cohen N, Goldberg VM, Caplan AI (2004) Targeted delivery of progenitor cells for cartilage repair. J Orthop Res 22:735–741PubMedCrossRefGoogle Scholar
  14. Ding Y, Xu D, Feng G, Bushell A, Muschel RJ, Wood KJ (2009) Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase-2 and -9. Diabetes 58:1797–1806PubMedCrossRefGoogle Scholar
  15. Dominici M, Le BK, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317PubMedCrossRefGoogle Scholar
  16. Dos Santos F, Andrade PZ, Boura JS, Abecasis MM, da Silva CL, Cabral JM (2010) Ex vivo expansion of human mesenchymal stem cells: a more effective cell proliferation kinetics and metabolism under hypoxia. J Cell Physiol 223:27–35PubMedGoogle Scholar
  17. Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP (1968) Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 6:230–247PubMedCrossRefGoogle Scholar
  18. Gatti S, Bruno S, Deregibus MC, Sordi A, Cantaluppi V, Tetta C, Camussi G (2011) Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury. Nephrol Dial Transplant 26:1474–1483PubMedCrossRefGoogle Scholar
  19. Glavaski-Joksimovic A, Virag T, Mangatu TA, McGrogan M, Wang XS, Bohn MC (2010) Glial cell line-derived neurotrophic factor-secreting genetically modified human bone marrow-derived mesenchymal stem cells promote recovery in a rat model of Parkinson’s disease. J Neurosci Res 88:2669–2681PubMedGoogle Scholar
  20. Gnecchi M, He H, Melo LG, Noiseaux N, Morello F, de Boer RA, Zhang L, Pratt RE, Dzau VJ, Ingwall JS (2009) Early beneficial effects of bone marrow-derived mesenchymal stem cells overexpressing Akt on cardiac metabolism after myocardial infarction. Stem Cells 27:971–979PubMedCrossRefGoogle Scholar
  21. Hicok KC, Hedrick MH (2011) Automated isolation and processing of adipose-derived stem and regenerative cells. Methods Mol Biol 702:87–105PubMedCrossRefGoogle Scholar
  22. Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, Deans RJ, Krause DS, Keating A (2005) Clarification of the nomenclature for MSC: the International Society for Cellular Therapy position statement. Cytotherapy 7:393–395PubMedCrossRefGoogle Scholar
  23. Humphreys BD, Bonventre JV (2008) Mesenchymal stem cells in acute kidney injury. Annu Rev Med 59:311–325PubMedCrossRefGoogle Scholar
  24. Humphreys BD, Valerius MT, Kobayashi A, Mugford JW, Soeung S, Duffield JS, McMahon AP, Bonventre JV (2008) Intrinsic epithelial cells repair the kidney after injury. Cell Stem Cell 2:284–291PubMedCrossRefGoogle Scholar
  25. Humphreys BD, Czerniak S, Dirocco DP, Hasnain W, Cheema R, Bonventre JV (2011) Repair of injured proximal tubule does not involve specialized progenitors. Proc Natl Acad Sci USA 108:9226–9231PubMedCrossRefGoogle Scholar
  26. Imberti B, Morigi M, Tomasoni S, Rota C, Corna D, Longaretti L, Rottoli D, Valsecchi F, Benigni A, Wang J, Abbate M, Zoja C, Remuzzi G (2007) Insulin-like growth factor-1 sustains stem cell-mediated renal repair. J Am Soc Nephrol 18:2921–2928PubMedCrossRefGoogle Scholar
  27. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418:41–49PubMedCrossRefGoogle Scholar
  28. Karp JM, Leng Teo GS (2009) Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell 4:206–216PubMedCrossRefGoogle Scholar
  29. Kogler G, Sensken S, Airey JA, Trapp T, Muschen M, Feldhahn N, Liedtke S, Sorg RV, Fischer J, Rosenbaum C, Greschat S, Knipper A, Bender J, Degistirici O, Gao J, Caplan AI, Colletti EJ, Meida-Porada G, Muller HW, Zanjani E, Wernet P (2004) A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med 200:123–135PubMedCrossRefGoogle Scholar
  30. Komarova S, Roth J, Alvarez R, Curiel DT, Pereboeva L (2010) Targeting of mesenchymal stem cells to ovarian tumors via an artificial receptor. J Ovarian Res 3:12PubMedCrossRefGoogle Scholar
  31. Kucia M, Reca R, Campbell FR, Zuba-Surma E, Majka M, Ratajczak J, Ratajczak MZ (2006) A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1(+)Oct-4+ stem cells identified in adult bone marrow. Leukemia 20:857–869PubMedCrossRefGoogle Scholar
  32. Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, Salto-Tellez M, Timmers L, Lee CN, El Oakley RM, Pasterkamp G, de Kleijn DP, Lim SK (2010) Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 4:214–222PubMedCrossRefGoogle Scholar
  33. Lakshmipathy U, Hart RP (2008) Concise review: microRNA expression in multipotent mesenchymal stromal cells. Stem Cells 26:356–363PubMedCrossRefGoogle Scholar
  34. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringdén O (2008) Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371:1579–1586PubMedCrossRefGoogle Scholar
  35. Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, Semprun-Prieto L, Delafontaine P, Prockop DJ (2009) Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 5:54–63PubMedCrossRefGoogle Scholar
  36. Li W, Ma N, Ong LL, Nesselmann C, Klopsch C, Ladilov Y, Furlani D, Piechaczek C, Moebius JM, Lutzow K, Lendlein A, Stamm C, Li RK, Steinhoff G (2007) Bcl-2 engineered MSCs inhibited apoptosis and improved heart function. Stem Cells 25:2118–2127PubMedCrossRefGoogle Scholar
  37. Liu H, Xue W, Ge G, Luo X, Li Y, Xiang H, Ding X, Tian P, Tian X (2010) Hypoxic preconditioning advances CXCR4 and CXCR7 expression by activating HIF-1alpha in MSCs. Biochem Biophys Res Commun 401:509–515PubMedCrossRefGoogle Scholar
  38. Lu D, Chen B, Liang Z, Deng W, Jiang Y, Li S, Xu J, Wu Q, Zhang Z, Xie B, Chen S (2011) Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial. Diabetes Res Clin Pract 92:26–36PubMedCrossRefGoogle Scholar
  39. Moodley Y, Atienza D, Manuelpillai U, Samuel CS, Tchongue J, Ilancheran S, Boyd R, Trounson A (2009) Human umbilical cord mesenchymal stem cells reduce fibrosis of bleomycin-induced lung injury. Am J Pathol 175:303–313PubMedCrossRefGoogle Scholar
  40. Morigi M, Imberti B, Zoja C, Corna D, Tomasoni S, Abbate M, Rottoli D, Angioletti S, Benigni A, Perico N, Alison M, Remuzzi G (2004) Mesenchymal stem cells are renotropic, helping to repair the kidney and improve function in acute renal failure. J Am Soc Nephrol 15:1794–1804PubMedCrossRefGoogle Scholar
  41. Nemeth K, Leelahavanichkul A, Yuen PST, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, Hu X, Jelinek I, Star RA, Mezey E (2009) Bone marrow stromal cells attenuate sepsis via prostaglandin E 2-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 15:42–49PubMedCrossRefGoogle Scholar
  42. Newman RE, Yoo D, LeRoux MA, Danilkovitch-Miagkova A (2009) Treatment of inflammatory diseases with mesenchymal stem cells. Inflamm Allergy Drug Targets 8:110–123PubMedCrossRefGoogle Scholar
  43. Ortiz LA, DuTreil M, Fattman C, Pandey AC, Torres G, Go K, Phinney DG (2007) Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci USA 104:11002–11007PubMedCrossRefGoogle Scholar
  44. Owen M (1988) Marrow stromal stem cells. J Cell Sci Suppl 10:63–76PubMedGoogle Scholar
  45. Pal R, Venkataramana NK, Bansal A, Balaraju S, Jan M, Chandra R, Dixit A, Rauthan A, Murgod U, Totey S (2009) Ex vivo-expanded autologous bone marrow-derived mesenchymal stromal cells in human spinal cord injury/paraplegia: a pilot clinical study. Cytotherapy 11:897–911PubMedCrossRefGoogle Scholar
  46. Sacchetti B, Funari A, Michienzi S, Di Cesare S, Piersanti S, Saggio I, Tagliafico E, Ferrari S, Robey PG, Riminucci M, Bianco P (2007) Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131:324–336PubMedCrossRefGoogle Scholar
  47. Sackstein R, Merzaban JS, Cain DW, Dagia NM, Spencer JA, Lin CP, Wohlgemuth R (2008) Ex vivo glycan engineering of CD44 programs human multipotent mesenchymal stromal cell trafficking to bone. Nat Med 14:181–187PubMedCrossRefGoogle Scholar
  48. Sarkar D, Zhao W, Gupta A, Loh WL, Karnik R, Karp JM (2011) Cell surface engineering of mesenchymal stem cells. Methods Mol Biol 698:505–523PubMedCrossRefGoogle Scholar
  49. Simmons PJ, Przepiorka D, Thomas ED, Torok-Storb B (1987) Host origin of marrow stromal cells following allogeneic bone marrow transplantation. Nature 328:429–432PubMedCrossRefGoogle Scholar
  50. Singer JW, Keating A, Cuttner J, Gown AM, Jacobson R, Killen PD, Moohr JW, Najfeld V, Powell J, Sanders J et al (1984) Evidence for a stem cell common to hematopoiesis and its in vitro microenvironment: studies of patients with clonal hematopoietic neoplasia. Leuk Res 8:535–545PubMedCrossRefGoogle Scholar
  51. Till JE, McCulloch EA (1961) A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 14:213–222PubMedCrossRefGoogle Scholar
  52. Timmers L, Lim SK, Hoefer IE, Arslan F, Lai RC, van Oorschot AA, Goumans MJ, Strijder C, Sze SK, Choo A, Piek JJ, Doevendans PA, Pasterkamp G, de Kleijn DP (2011) Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction. Stem Cell Res 6:206–214PubMedCrossRefGoogle Scholar
  53. Togel FE, Westenfelder C (2010) Mesenchymal stem cells: a new therapeutic tool for AKI. Nat Rev Nephrol 6:179–183PubMedCrossRefGoogle Scholar
  54. Togel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C (2005) Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 289:F31–F42PubMedCrossRefGoogle Scholar
  55. Togel F, Zhang P, Hu Z, Westenfelder C (2009) VEGF is a mediator of the renoprotective effects of multipotent marrow stromal cells in acute kidney injury. J Cell Mol Med 13:2109–2114PubMedCrossRefGoogle Scholar
  56. Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD (2002) Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 105:93–98PubMedCrossRefGoogle Scholar
  57. Uccelli A, Moretta L, Pistoia V (2008) Mesenchymal stem cells in health and disease. Nat Rev Immunol 8:726–736PubMedCrossRefGoogle Scholar
  58. Wagner J, Kean T, Young R, Dennis JE, Caplan AI (2009) Optimizing mesenchymal stem cell-based therapeutics. Curr Opin Biotechnol 20:531–536PubMedCrossRefGoogle Scholar
  59. Westergren-Thorsson G, Larsen K, Nihlberg K, Andersson-Sjoland A, Hallgren O, Marko-Varga G, Bjermer L (2010) Pathological airway remodelling in inflammation. Clin Respir J 4(Suppl 1):1–8PubMedCrossRefGoogle Scholar
  60. Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214:199–210PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  1. 1.Pharma Research and Early Development (pRED)Roche Diagnostics GmbHPenzbergGermany

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