Preclinical and Clinical Evidence of Mycobacterium tuberculosis Persistence in the Hypoxic Niche of Bone Marrow Mesenchymal Stem Cells after Therapy

• Published in: The American journal of pathology Vol. 185; no. 7; pp. 1924 - 1934
• Main Authors: Garhyan, Jaishree, Bhuyan, Seema, Pulu, Ista, Kalita, Deepjyoti, Das, Bikul, Bhatnagar, Rakesh
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2015
• Subjects: Adapalene - immunology; Animals; Antitubercular Agents - therapeutic use; Bone Marrow Cells - immunology; Bone Marrow Cells - microbiology; Cell Hypoxia; Down-Regulation; Female; Green Fluorescent Proteins; Humans; Isoniazid - therapeutic use; Lung - microbiology; Lung - pathology; Mesenchymal Stromal Cells - immunology; Mesenchymal Stromal Cells - microbiology; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis - pathogenicity; Mycobacterium tuberculosis - physiology; Nitroimidazoles; Pathology; Radiation-Sensitizing Agents; Specific Pathogen-Free Organisms; Tuberculosis, Pulmonary - drug therapy; Tuberculosis, Pulmonary - microbiology; Tuberculosis, Pulmonary - pathology; Up-Regulation
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2015.03.028

Mycobacterium tuberculosis (MTB), the causative agent of pulmonary tuberculosis, is difficult to eliminate by antibiotic therapy. We recently identified CD271+ bone marrow–mesenchymal stem cells (BM-MSCs) as a potential site of MTB persistence after therapy. Herein, we have characterized the potential hypoxic localization of the post-therapy MTB-infected CD271+ BM-MSCs in both mice and human subjects. We first demonstrate that in a Cornell model of MTB persistence in mice, green fluorescent protein–labeled virulent MTB-strain H37Rv was localized to pimonidazole (an in vivo hypoxia marker) positive CD271+ BM-MSCs after 90 days of isoniazid and pyrazinamide therapy that rendered animal's lung noninfectious. The recovered CD271+ BM-MSCs from post-therapy mice, when injected into healthy mice, caused active tuberculosis infection in the animal's lung. Moreover, MTB infection significantly increased the hypoxic phenotype of CD271+ BM-MSCs. Next, in human subjects, previously treated for pulmonary tuberculosis, the MTB-containing CD271+ BM-MSCs exhibited high expression of hypoxia-inducible factor 1α and low expression of CD146, a hypoxia down-regulated cell surface marker of human BM-MSCs. These data collectively demonstrate the potential localization of MTB harboring CD271+ BM-MSCs in the hypoxic niche, a critical microenvironmental factor that is well known to induce the MTB dormancy phenotype.