Information

Related Research Units

Nephrology Research

Research Overview

Dr. Frank's laboratory research, conducted in the Transplantation Research Program of Boston Children's Hospital and the Department of Dermatology at Brigham and Women's Hospital, focuses on the physiological and pathological roles of ATP-binding cassette, sub-family B, member 5 (ABCB5) in normal tissue-specific stem cells and malignant cancer stem cells.

Stem Cell Therapeutics

 Dr. Frank's laboratory has cloned and characterized a novel human P-glycoprotein family member, ABCB5, which regulates maintenance and differentiation of normal tissue-specific stem cells with therapeutic capacity as a transplantable cell source for immunomodulation (Schatton et al. Cell Reports 2015) and tissue regeneration, as shown, for example, in a first report of constructing a fully functional human tissue (cornea) from molecularly defined adult stem cells (Ksander et al. Nature 2014). As a result of these discoveries, advanced EMA- and/or FDA-approved human clinical trials are currently underway to translate ABCB5+ dermal mesenchymal stem cell (DMSC)- and ABCB5+ limbal stem cell (LSC)-based strategies to novel therapies for multiple disorders of aberrant immune activation and tissue regeneration (ClinicalTrials.gov Identifiers: NCT04971161 – chronic venous ulcer disease (CVU); NCT03549299 – limbal stem cell deficiency (LSCD); NCT03529877 – recessive dystrophic epidermolysis bullosa (RDEB)), with initial successful clinical results in cutaneous wound healing and RDEB now already available (Kerstan et al. JID Innovations 2021 - in press; Kiritsis et al. JCI Insight 2021 - in press). Additionally, Germany’s Federal Institute for Vaccines and Biomedicines (Paul-Ehrlich-Institut) recently granted national approval for allogeneic ABCB5+ DMSCs (AMESANAR®) as an Advanced Therapy Medicinal Product (ATMP) for treatment of chronic wounds in patients with chronic venous insufficiency.

Cancer Stem Cell-Targeted Therapeutic Strategies

Dr. Frank's laboratory has also shown that ABCB5 serves as a multidrug resistance transporter in cancer stem cells of several human malignancies, including malignant melanoma, colorectal cancer and glioblastoma, conferring resistance to chemotherapy. Specifically, his laboratory's work has shown that 1) ABCB5 marks malignant melanoma subpopulations of cancer stem cell phenotype and function that possess specific roles in the evasion of antitumor immunity and tumor-promoting vasculogenic mimicry; 2) ABCB5 correlates with cancer progression in melanoma, colorectal cancer and glioblastoma patients and serves as a prognostic marker of disease progression or recurrence; and 3) ABCB5 can be therapeutically targeted to inhibit tumor growth (Schatton et al. Nature 2008, cover article). These findings established for the first time proof-of-principle for the potential therapeutic utility of the cancer stem cell concept and hence have provided a key rationale for the development and clinical translation of cancer stem cell- targeted therapeutic strategies. Therefore, efforts are currently underway to further develop fully human high-affinity ABCB5 monoclonal antibodies as novel cancer stem cell-targeted drug candidates for clinical therapy.

Research Background

Markus Frank is Associate Professor of Pediatrics and of Dermatology at Harvard Medical School, Associate Physician in the Renal Division at Brigham and Women's Hospital, a member of the Stem Cell Program at Boston Children's Hospital, and Co-Leader of the Harvard Stem Cell Institute Skin Program. Dr. Frank received a Bachelor’s degree in Biochemical Sciences from Harvard College and an M.D. degree from the University of Heidelberg School of Medicine, Germany. He completed a residency in Internal Medicine at Albert Einstein College of Medicine in New York and a fellowship in Nephrology at Brigham and Women's Hospital, followed by research training in transplant immunology at Brigham and Women's Hospital and Boston Children's Hospital. He is an elected member of the American Society for Clinical Investigation (ASCI).

Publications

  1. Systemic treatment of recessive dystrophic epidermolysis bullosa with mesenchymal stromal cells: a scoping review of the literature and conclusions for future clinical research. J Dermatolog Treat. 2024 Dec; 35(1):2419931. View Abstract
  2. Anti-Inflammatory and Anti-(Lymph)angiogenic Properties of an ABCB5+ Limbal Mesenchymal Stem Cell Population. Int J Mol Sci. 2024 Sep 07; 25(17). View Abstract
  3. Potency assay to predict the anti-inflammatory capacity of a cell therapy product for macrophage-driven diseases: overcoming the challenges of assay development and validation. Cytotherapy. 2024 05; 26(5):512-523. View Abstract
  4. Accelerated Aging and Microsatellite Instability in Recessive Dystrophic Epidermolysis Bullosa-Associated Cutaneous Squamous Cell Carcinoma. J Invest Dermatol. 2024 Jul; 144(7):1534-1543.e2. View Abstract
  5. Clinical-grade human skin-derived ABCB5+ mesenchymal stromal cells exert anti-apoptotic and anti-inflammatory effects in vitro and modulate mRNA expression in a cisplatin-induced kidney injury murine model. Front Immunol. 2023; 14:1228928. View Abstract
  6. Protocol for isolating human BCAM-positive corneal progenitor cells by flow cytometry and cell sorting. STAR Protoc. 2023 Sep 15; 4(3):102503. View Abstract
  7. Corrigendum to ABCB5+ mesenchymal stromal cells facilitate complete and durable wound closure in recessive dystrophic epidermolysis bullosa [Cytotherapy 25 (2023) 782-788/1562]. Cytotherapy. 2023 Sep; 25(9):1016. View Abstract
  8. Drug Regulatory-Compliant Validation of a qPCR Assay for Bioanalysis Studies of a Cell Therapy Product with a Special Focus on Matrix Interferences in a Wide Range of Organ Tissues. Cells. 2023 07 05; 12(13). View Abstract
  9. ABCB5+ Limbal Epithelial Stem Cells Inhibit Developmental but Promote Inflammatory (Lymph) Angiogenesis While Preventing Corneal Inflammation. Cells. 2023 06 27; 12(13). View Abstract
  10. Kinetics of Wound Development and Healing Suggests a Skin-Stabilizing Effect of Allogeneic ABCB5+ Mesenchymal Stromal Cell Treatment in Recessive Dystrophic Epidermolysis Bullosa. Cells. 2023 05 24; 12(11). View Abstract
  11. ABCB5+ mesenchymal stromal cells facilitate complete and durable wound closure in recessive dystrophic epidermolysis bullosa. Cytotherapy. 2023 07; 25(7):782-788. View Abstract
  12. ABCB5+ mesenchymal stromal cells therapy protects from hypoxia by restoring Ca2+ homeostasis in vitro and in vivo. Stem Cell Res Ther. 2023 02 09; 14(1):24. View Abstract
  13. Epigenetic Regulation of Corneal Epithelial Differentiation by TET2. Int J Mol Sci. 2023 Feb 02; 24(3). View Abstract
  14. Skin-Derived ABCB5+ Mesenchymal Stem Cells for High-Medical-Need Inflammatory Diseases: From Discovery to Entering Clinical Routine. Int J Mol Sci. 2022 Dec 21; 24(1). View Abstract
  15. Consecutive dosing of UVB irradiation induces loss of ABCB5 expression and activation of EMT and fibrosis proteins in limbal epithelial cells similar to pterygium epithelium. Stem Cell Res. 2022 10; 64:102936. View Abstract
  16. Translational development of ABCB5+ dermal mesenchymal stem cells for therapeutic induction of angiogenesis in non-healing diabetic foot ulcers. Stem Cell Res Ther. 2022 09 05; 13(1):455. View Abstract
  17. Limbal BCAM expression identifies a proliferative progenitor population capable of holoclone formation and corneal differentiation. Cell Rep. 2022 08 09; 40(6):111166. View Abstract
  18. Clinical trial of ABCB5+ mesenchymal stem cells for recessive dystrophic epidermolysis bullosa. JCI Insight. 2021 11 22; 6(22). View Abstract
  19. Angiogenin Released from ABCB5+ Stromal Precursors Improves Healing of Diabetic Wounds by Promoting Angiogenesis. J Invest Dermatol. 2022 06; 142(6):1725-1736.e10. View Abstract
  20. Allogeneic ABCB5+ mesenchymal stem cells for treatment-refractory chronic venous ulcers: a phase I/IIa clinical trial. JID Innov. 2022 Jan; 2(1). View Abstract
  21. High expression of SARS-CoV2 viral entry-related proteins in human limbal stem cells. Ocul Surf. 2022 01; 23:197-200. View Abstract
  22. Human iPS cells engender corneal epithelial stem cells with holoclone-forming capabilities. iScience. 2021 Jun 25; 24(6):102688. View Abstract
  23. Process development and safety evaluation of ABCB5+ limbal stem cells as advanced-therapy medicinal product to treat limbal stem cell deficiency. Stem Cell Res Ther. 2021 03 19; 12(1):194. View Abstract
  24. ABCB5+ dermal mesenchymal stromal cells with favorable skin homing and local immunomodulation for recessive dystrophic epidermolysis bullosa treatment. Stem Cells. 2021 07; 39(7):897-903. View Abstract
  25. Clinical Implications of Colorectal Cancer Stem Cells in the Age of Single-Cell Omics and Targeted Therapies. Gastroenterology. 2021 05; 160(6):1947-1960. View Abstract
  26. Process data of allogeneic ex vivo-expanded ABCB5+ mesenchymal stromal cells for human use: off-the-shelf GMP-manufactured donor-independent ATMP. Stem Cell Res Ther. 2020 11 16; 11(1):482. View Abstract
  27. Ex vivo-expanded highly pure ABCB5+ mesenchymal stromal cells as Good Manufacturing Practice-compliant autologous advanced therapy medicinal product for clinical use: process validation and first in-human data. Cytotherapy. 2021 02; 23(2):165-175. View Abstract
  28. Targeting the ABC transporter ABCB5 sensitizes glioblastoma to temozolomide-induced apoptosis through a cell-cycle checkpoint regulation mechanism. J Biol Chem. 2020 05 29; 295(22):7774-7788. View Abstract
  29. Loss of the Epigenetic Mark 5-hmC in Psoriasis: Implications for Epidermal Stem Cell Dysregulation. J Invest Dermatol. 2020 06; 140(6):1266-1275.e3. View Abstract
  30. PD-L1 Expression on Circulating Tumor Cells May Be Predictive of Response to Pembrolizumab in Advanced Melanoma: Results from a Pilot Study. Oncologist. 2020 03; 25(3):e520-e527. View Abstract
  31. PD-L1 Expression on Circulating Tumor Cells May Be Predictive of Response to Pembrolizumab in Advanced Melanoma: Results from a Pilot Study. Oncologist. 2019 Dec 05. View Abstract
  32. Correction to: Human skin-derived ABCB5+ stem cell injection improves liver disease parameters in Mdr2KO mice. Arch Toxicol. 2019 Dec; 93(12):3669-3670. View Abstract
  33. Investigation of factors associated with ABCB5-positive limbal stem cell isolation yields from human donors. Ocul Surf. 2020 01; 18(1):114-120. View Abstract
  34. Newly Defined ATP-Binding Cassette Subfamily B Member 5 Positive Dermal Mesenchymal Stem Cells Promote Healing of Chronic Iron-Overload Wounds via Secretion of Interleukin-1 Receptor Antagonist. Stem Cells. 2019 08; 37(8):1057-1074. View Abstract
  35. In vivo safety profile and biodistribution of GMP-manufactured human skin-derived ABCB5-positive mesenchymal stromal cells for use in clinical trials. Cytotherapy. 2019 05; 21(5):546-560. View Abstract
  36. Immunomagnetic-Enriched Subpopulations of Melanoma Circulating Tumour Cells (CTCs) Exhibit Distinct Transcriptome Profiles. Cancers (Basel). 2019 Jan 30; 11(2). View Abstract
  37. UV light-blocking contact lenses protect against short-term UVB-induced limbal stem cell niche damage and inflammation. Sci Rep. 2018 08 22; 8(1):12564. View Abstract
  38. ATP-binding cassette member B5 (ABCB5) promotes tumor cell invasiveness in human colorectal cancer. J Biol Chem. 2018 07 13; 293(28):11166-11178. View Abstract
  39. Repairing the corneal epithelium using limbal stem cells or alternative cell-based therapies. Expert Opin Biol Ther. 2018 05; 18(5):505-513. View Abstract
  40. [Stem cell-based strategies in vascular surgery]. Gefasschirurgie. 2018 Feb; 23(1):28-33. View Abstract
  41. Limbal stem cells: identity, developmental origin, and therapeutic potential. Wiley Interdiscip Rev Dev Biol. 2018 03; 7(2). View Abstract
  42. Detection of ABCB5 tumour antigen-specific CD8+ T cells in melanoma patients and implications for immunotherapy. Clin Exp Immunol. 2018 01; 191(1):74-83. View Abstract
  43. Rapid generation of Col7a1-/- mouse model of recessive dystrophic epidermolysis bullosa and partial rescue via immunosuppressive dermal mesenchymal stem cells. Lab Invest. 2017 10; 97(10):1218-1224. View Abstract
  44. Isolation and detection of circulating tumour cells from metastatic melanoma patients using a slanted spiral microfluidic device. Oncotarget. 2017 Sep 15; 8(40):67355-67368. View Abstract
  45. Isolation and detection of circulating tumour cells from metastatic melanoma patients using a slanted spiral microfluidic device. Oncotarget. 2017 Jun 27. View Abstract
  46. Expression of Cell-Surface Marker ABCB5 Causes Characteristic Modifications of Glucose, Amino Acid and Phospholipid Metabolism in the G3361 Melanoma-Initiating Cell Line. PLoS One. 2016; 11(8):e0161803. View Abstract
  47. Suppression of Neutrophil-Mediated Tissue Damage-A Novel Skill of Mesenchymal Stem Cells. Stem Cells. 2016 09; 34(9):2393-406. View Abstract
  48. ABCB5-Targeted Chemoresistance Reversal Inhibits Merkel Cell Carcinoma Growth. J Invest Dermatol. 2016 Apr; 136(4):838-846. View Abstract
  49. Effects of Malignant Melanoma Initiating Cells on T-Cell Activation. Methods Mol Biol. 2016 Jan 20. View Abstract
  50. Isolation of Circulating Melanoma Cells. Methods Mol Biol. 2015 Sep 29. View Abstract
  51. Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth. Cell. 2015 Sep 10; 162(6):1242-56. View Abstract
  52. ABCB5 Identifies Immunoregulatory Dermal Cells. Cell Rep. 2015 Sep 08; 12(10):1564-74. View Abstract
  53. Circulating Melanoma Cell Subpopulations: Their Heterogeneity and Differential Responses to Treatment. J Invest Dermatol. 2015 Aug; 135(8):2040-2048. View Abstract
  54. Expression of Multidrug Resistance Transporter ABCB5 in a Murine Model of Human Conjunctival Melanoma. Ocul Oncol Pathol. 2015 Apr; 1(3):182-189. View Abstract
  55. Restoring the cornea from limbal stem cells. Regen Med. 2015; 10(1):1-4. View Abstract
  56. Nestin depletion induces melanoma matrix metalloproteinases and invasion. Lab Invest. 2014 Dec; 94(12):1382-95. View Abstract
  57. ABCB5 is a limbal stem cell gene required for corneal development and repair. Nature. 2014 Jul 17; 511(7509):353-7. View Abstract
  58. ABCB5 maintains melanoma-initiating cells through a proinflammatory cytokine signaling circuit. Cancer Res. 2014 Aug 01; 74(15):4196-207. View Abstract
  59. The multidrug-resistance transporter ABCB5 is expressed in human placenta. Int J Gynecol Pathol. 2014 Jan; 33(1):45-51. View Abstract
  60. Stem cells and targeted approaches to melanoma cure. Mol Aspects Med. 2014 Oct; 39:33-49. View Abstract
  61. Genetically determined ABCB5 functionality correlates with pigmentation phenotype and melanoma risk. Biochem Biophys Res Commun. 2013 Jul 05; 436(3):536-42. View Abstract
  62. Markers of circulating tumour cells in the peripheral blood of patients with melanoma correlate with disease recurrence and progression. Br J Dermatol. 2013 Jan; 168(1):85-92. View Abstract
  63. Synergy of photoacoustic and fluorescence flow cytometry of circulating cells with negative and positive contrasts. J Biophotonics. 2013 May; 6(5):425-34. View Abstract
  64. Metabolic inhibition of galectin-1-binding carbohydrates accentuates antitumor immunity. J Invest Dermatol. 2012 Feb; 132(2):410-20. View Abstract
  65. ABCB5 identifies a therapy-refractory tumor cell population in colorectal cancer patients. Cancer Res. 2011 Aug 01; 71(15):5307-16. View Abstract
  66. Colorectal Cancer Stem Cells: Biology and Therapeutic Implications. Curr Colorectal Cancer Rep. 2011 Jun; 7(2):128-135. View Abstract
  67. The pro-apoptotic protein Bim is a microRNA target in kidney progenitors. J Am Soc Nephrol. 2011 Jun; 22(6):1053-63. View Abstract
  68. SOX2 and nestin expression in human melanoma: an immunohistochemical and experimental study. Exp Dermatol. 2011 Apr; 20(4):339-45. View Abstract
  69. VEGFR-1 expressed by malignant melanoma-initiating cells is required for tumor growth. Cancer Res. 2011 Feb 15; 71(4):1474-85. View Abstract
  70. Isolation of tumorigenic circulating melanoma cells. Biochem Biophys Res Commun. 2010 Nov 26; 402(4):711-7. View Abstract
  71. The in vitro spheroid melanoma cell culture assay: cues on tumor initiation? J Invest Dermatol. 2010 Jul; 130(7):1769-71. View Abstract
  72. A novel in vivo regulatory role of P-glycoprotein in alloimmunity. Biochem Biophys Res Commun. 2010 Apr 09; 394(3):646-52. View Abstract
  73. Tumor initiation in human malignant melanoma and potential cancer therapies. Anticancer Agents Med Chem. 2010 Feb; 10(2):131-6. View Abstract
  74. Modulation of T-cell activation by malignant melanoma initiating cells. Cancer Res. 2010 Jan 15; 70(2):697-708. View Abstract
  75. The therapeutic promise of the cancer stem cell concept. J Clin Invest. 2010 Jan; 120(1):41-50. View Abstract
  76. A gene encoding a multidrug-resistance human P-glycoprotein homologue on chromosome 7p15-2 and uses thereof. 2009. View Abstract
  77. Identification and targeting of cancer stem cells. Bioessays. 2009 Oct; 31(10):1038-49. View Abstract
  78. Antitumor immunity and cancer stem cells. Ann N Y Acad Sci. 2009 Sep; 1176:154-69. View Abstract
  79. ABCB5 gene amplification in human leukemia cells. Leuk Res. 2009 Oct; 33(10):1303-5. View Abstract
  80. Identifizierung tumorinitiierender Zellen im Pankreaskarzinom: Untersuchung zur Bedeutung des MDR-Gens ABCB5. 126. Kongress der Deutschen Gesellschaft für Chirurgie, 28.04. - 01.05.2009, München. 2009; DOI: 10.3205/09dgch095. View Abstract
  81. Detection and Quantification of Circulating Melanoma Cells. 7th World Congress on Melanoma, May 12 -16 2009, Vienna, Austria. 2009; 123. View Abstract
  82. Tumour-Promoting Vasculogenic Channels of Cancer Stem Cell Origin. 7th World Congress on Melanoma, May 12 -16 2009, Vienna, Austria. 2009; 191. View Abstract
  83. Inhibition of T cell activation by melanoma stem cells. 7th World Congress on Melanoma, May 12 -16 2009, Vienna, Austria. 2009; 191-192. View Abstract
  84. Melanoma vasculogenesis driven by cancer stem cells. Proceedings of the American Association for Cancer Research 100th Annual Meeting 2009, Denver, Colorado. 2009; 50(April 2009):759 (Abstract #3131). View Abstract
  85. Cancer stem cell-mediated immunomodulation in human malignant melanoma. Proceedings of the American Association for Cancer Research 100th Annual Meeting 2009, Denver, Colorado. 2009; 50(April 2009):765 (Abstract #3164). View Abstract
  86. Solid tumor stem cells – implications for cancer therapy. Regulatory Networks in Stem Cells. 2009. View Abstract
  87. Solid tumor stem cells – implications for cancer therapy. Regulatory Networks in Stem Cells (V.K. Rajasekhar and M.C. Vemuri, Editors.). 2009; 527-543. View Abstract
  88. The effects of tamoxifen on immunity. Curr Med Chem. 2009; 16(24):3076-80. View Abstract
  89. Gene encoding a multidrug resistance human P-glycoprotein homologue on chromosome 7p15-21 and uses thereof. 2008. View Abstract
  90. Gene encoding a multidrug-resistance human P-glycoprotein homologue on chromosome 7p15-2 and uses thereof. 2008. View Abstract
  91. Therapeutic and diagnostic methods relating to cancer stem cells. 2008. View Abstract
  92. Identification of cells initiating human melanomas. International Investigative Dermatology 2008 Meeting. 2008; Kyoto, Japan May 14-17 2008. View Abstract
  93. Identification of cells initiating human melanomas. AACR Annual Meeting 2008. 2008; San Diego, CA, USA April 12-16. View Abstract
  94. Cancer stem cells and human malignant melanoma. Pigment Cell Melanoma Res. 2008 Feb; 21(1):39-55. View Abstract
  95. Identification of cells initiating human melanomas. Nature. 2008 Jan 17; 451(7176):345-9. View Abstract
  96. ABCB5 positive mesenchymal stem cells as immunomodulators. 2007. View Abstract
  97. Targeting ABCB5 for cancer therapy. 2007. View Abstract
  98. P-glycoprotein functions as a differentiation switch in antigen presenting cell maturation. Am J Transplant. 2006 Dec; 6(12):2884-93. View Abstract
  99. Regulation of myogenic progenitor proliferation in human fetal skeletal muscle by BMP4 and its antagonist Gremlin. J Cell Biol. 2006 Oct 09; 175(1):99-110. View Abstract
  100. Investigation of multidrug resistance in cultured human renal cell carcinoma cells by 31P-NMR spectroscopy and treatment survival assays. MAGMA. 2005 Jul; 18(3):144-61. View Abstract
  101. ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res. 2005 May 15; 65(10):4320-33. View Abstract
  102. A gene encoding a multidrug resistance human P-glycoprotein homologue on chromosome 7p15-21 and uses thereof. 2005. View Abstract
  103. CD40-induced transcriptional activation of vascular endothelial growth factor involves a 68-bp region of the promoter containing a CpG island. Am J Physiol Renal Physiol. 2004 Sep; 287(3):F512-20. View Abstract
  104. Immunomodulatory functions of mesenchymal stem cells. Lancet. 2004 May 01; 363(9419):1411-2. View Abstract
  105. Regulation of progenitor cell fusion by ABCB5 P-glycoprotein, a novel human ATP-binding cassette transporter. J Biol Chem. 2003 Nov 21; 278(47):47156-65. View Abstract
  106. P-glycoprotein--a novel therapeutic target for immunomodulation in clinical transplantation and autoimmunity? Curr Drug Targets. 2003 Aug; 4(6):469-76. View Abstract
  107. P-glycoprotein and alloimmune T-cell activation. Clin Appl Immunol Rev. 2003 Jul; 4(1):3-14. View Abstract
  108. Specific MDR1 P-glycoprotein blockade inhibits human alloimmune T cell activation in vitro. J Immunol. 2001 Feb 15; 166(4):2451-9. View Abstract
  109. Tolerance: is it time to move to the clinic?. Current and Future Immunosuppressive Therapies Following Transplantation. 2001; 293-313. View Abstract
  110. Monoclonal Antibody Targeting of Adhesion Molecules. Current and Future Immunosuppressive Therapies Following Transplantation. 2001; 249-263. View Abstract
  111. Interferon alpha2b differentially affects proliferation of two human renal cell carcinoma cell lines differing in the P-glycoprotein-associated multidrug-resistant phenotype. J Cancer Res Clin Oncol. 1999; 125(2):117-20. View Abstract
  112. [Reversible esophageal dysfunction as a side effect of levodopa]. Bildgebung. 1996 Mar; 63(1):48-50. View Abstract
  113. 31P-NMR-spektroskopische Studien zur Multidrug-Resistenz des menschlichen Nierenzellkarzinoms [Doctoral Dissertation]. 1995. View Abstract

Contact Markus Frank

Phone: 617-919-2993
Print Profile