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

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.