ABCB5 in a Nutshell

Scientific Facts Regarding ABCB5 Expression in Normal Tissue-Specific Stem Cells

  • Among embryonic stem cells, ABCB5-expressing cells comprise a totipotent subpopulation comparable to early embryonic cells that co-express embryonic and extraembryonic determinants (1, 2).
  • During development, ABCB5 is expressed in extraembryonic tissue by trophoblasts (3).
  • In the adult organism, mammalian skin contains dermal stem cells with multipotent differentiation potential (4-6), including melanocytic differentiation potential.
  • ABCB5 was demonstrated to mark human skin-derived melanocytic precursors, i.e. ABCB5+ progenitor cells that preferentially co-express the stem cell marker CD133 (7).
  • ABCB5+ skin-derived stem cells were identified to possess multipotent differentiation plasticity (8).
  • A different group of investigators confirmed ABCB5+ skin-associated cell subpopulations to represent bona-fide dermal mesenchymal stem cells (MSCs) (9). Furthermore, in these studies, ABCB5+ dermal MSCs contributed to full-thickness excisional skin wound healing in mice to a comparable level as GMP-isolated and cultured bone-marrow derived MSCs. Additionally, it was demonstrated that ABCB5+ dermal MSCs secreted interleukin-1 receptor antagonist (IL-1RA) in response to inflammatory stimulation, which in turn inhibited classical macrophage activation with TNF-alpha release. IL1-RA inhibits the activity of IL-1 cytokines by binding to the IL-1 receptors without activating signal transduction. The importance of MSC-secreted IL-1RA for the observed accelerated cutaneous wound healing in mice was substantiated by a siRNA-mediated gene-silencing approach. In conclusion, human dermal ABCB5+ sorted MSCs represent an easy accessible source for cell-based therapy of skin wounds that accelerates healing at least in part by the secretion of IL-1RA.
  • In additional studies, ABCB5 was also identified as a subpopulation of dermal mesenchymal stem cells, with therapeutic immunoregulatory functions mediated through PD-1 (10) for future therapeutic use or cure for certain diseases.
  • In studies of the human and murine eye, ABCB5 was shown to be required for normal corneal and retinal development (11). Specifically, ABCB5 was demonstrated in this study to mark a subpopulation of corneal epithelial stem cells, i.e. limbal stem cells, which were exclusively capable of restoring a fully functional cornea upon transplantation to mice with induced limbal stem cell deficiency (11). These findings also revealed that ABCB5 is required for normal stem cell maintenance through anti-apoptotic functions (11).
  • Ex-vivo cultured limbal stem cell subpopulations also express ABCB5 (12).

These findings provide an outstanding scientific rationale for the future use of ABCB5+ stem cells in multiple therapeutic / clinical applications: For example, based on the immunomodulatory functions of ABCB5+ stem cells, organ transplant rejection, graft-versus-host-disease and auto-immune disorders such as inflammatory bowel disease, multiple sclerosis and type I diabetes mellitus might represent potential target indications for ABCB5+ mesenchymal stem cell therapy.

Additionally, due to the differentiation plasticity of ABCB5+ stem cells, multiple future therapeutic indications for tissue regeneration can be envisioned, such as for example in cutaneous wound healing and limbal stem cell deficiency, where proof-of-principle for therapeutic efficacy has already been established.

  1. Macfarlan TS, Gifford WD, Driscoll S, Lettieri K, Rowe HM, Bonanomi D, Firth A, Singer O, Trono D, and Pfaff SL. Embryonic stem cell potency fluctuates with endogenous retrovirus activity. Nature. 2012;487(7405):57-63.
  2. Morgani SM, Canham MA, Nichols J, Sharov AA, Migueles RP, Ko MS, and Brickman JM. Totipotent embryonic stem cells arise in ground-state culture conditions. Cell Rep. 2013;3(6):1945-57.
  3. Volpicelli ER, Lezcano C, Zhan Q, Girouard SD, Kindelberger DW, Frank MH, Frank NY, Crum CP, and Murphy GF. The multidrug-resistance transporter ABCB5 is expressed in human placenta. Int J Gynecol Pathol. 2014;33(1):45-51.
  4. Joannides A, Gaughwin P, Schwiening C, Majed H, Sterling J, Compston A, and Chandran S. Efficient generation of neural precursors from adult human skin: astrocytes promote neurogenesis from skin-derived stem cells. Lancet. 2004;364(9429):172-8.
  5. Li L, Fukunaga-Kalabis M, Yu H, Xu X, Kong J, Lee JT, and Herlyn M. Human dermal stem cells differentiate into functional epidermal melanocytes. J Cell Sci. 2010;123(Pt 6):853-60.
  6. Toma JG, Akhavan M, Fernandes KJ, Barnabe-Heider F, Sadikot A, Kaplan DR, and Miller FD. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nat Cell Biol. 2001;3(9):778-84.
  7. Frank NY, Pendse SS, Lapchak PH, Margaryan A, Shlain D, Doeing C, Sayegh MH, and Frank MH. Regulation of progenitor cell fusion by ABCB5 P-glycoprotein, a novel human ATP-binding cassette transporter. J Biol Chem. 2003;278(47):47156-65.
  8. Frank MH. United States Patent 8,455,245: The Brigham and Women's Hospital, Inc.;2013 Jun 4.
  9. Vander Beken S, Jiang D, Qi Y, de Vries J, Kluth A, Ziouta Y, Ganss C, Wlaschek M, and Scharffetter-Kochanek K. Human dermis-derived ABCB5-positive mesenchymal stem cells accelerate mouse skin full-thickness excisional wound healing in part by the secretion of interleukin-1 receptor antagonist. Journal of Investigative Dermatology. 2013;133(S247–S259):Abstract 1454.
  10. Schatton T, Yang J, Kleffel S, Uehara M, Barthel SR, Schlapbach C, Zhan Q, Dudeney S, Mueller H, Lee N, et al. ABCB5 Identifies Immunoregulatory Dermal Cells. Cell Rep. 2015;12(10):1564-74.
  11. Ksander BR, Kolovou PE, Wilson BJ, Saab KR, Guo Q, Ma J, McGuire SP, Gregory MS, Vincent WJ, Perez VL, et al. ABCB5 is a limbal stem cell gene required for corneal development and repair. Nature. 2014;511(7509):353-7.
  12. Kureshi AK, Dziasko M, Funderburgh JL, and Daniels JT. Human corneal stromal stem cells support limbal epithelial cells cultured on RAFT tissue equivalents. Sci Rep. 2015;5(16186).

 

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Clinical Trials

We are now also recruiting patients for further clinical studies in phase I/IIa with allogeneic ABCB5-positive (ABCB5+) mesenchymal stem cells for the following indications: chronic venous ulcer (CVU), diabetic foot ulcer (DFU) and peripheral arterial occlusive disease (PAOD). For more information click HERE.

License

Besides the authorization to manufacture a human medicinal product in accordance with § 13 (1) of the German Medicinal Products Act (AMG) for autologous mesenchymal stem cells, TICEBA is also authorized to manufacture a medicinal product for allogeneic mesenchymal as well as allogeneic limbal ABCB5 + stem cells following a recent extension. For more information click HERE.

The Story of Stem Cells

Review our category "The Story of Stem Cells" with the newest topic "Stem cells in wound healing" HERE.

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