Publications

Mesenchymal stem cells (MSCs) have been shown to have potent therapeutic effects in a number of disorders including traumatic brain injury (TBI). However, the molecular mechanism(s) underlying these protective effects are largely unknown. Herein we demonstrate that tissue inhibitor of matrix metalloproteinase-3 (TIMP3), a soluble protein released by MSCs, is neuroprotective and enhances neuronal survival and neurite outgrowth in vitro. In vivo in a murine model of TBI, intravenous recombinant TIMP3 enhances dendritic outgrowth and abrogates loss of hippocampal neural stem cells and mature neurons. Mechanistically we demonstrate in vitro and in vivo that TIMP3-mediated neuroprotection is critically dependent on activation of the Akt-mTORC1 pathway. In support of the neuroprotective effect of TIMP3, we find that intravenous delivery of recombinant TIMP3 attenuates deficits in hippocampal-dependent neurocognition. Taken together, our data strongly suggest that TIMP3 has direct neuroprotective effects that can mitigate the deleterious effects associated with TBI, an area with few if any therapeutic options.

A CD8+ cell non-cytotoxic antiviral response (CNAR), mediated by a CD8+ cell antiviral factor (CAF), is associated with a long-term healthy state in human immunodeficiency virus (HIV) infection. CNAR/CAF reduces viral transcription without a known effect on specific viral sequences in the HIV genome. In studies to define the mechanism involved in the block in viral transcription, we now report that transcription from the HIV-LTR reporter is reduced in infected CD4+ cells upon treatment with CAF. In agreement with this observation, the amount of RNA polymerase II (RNAPII) on the HIV promoter and other viral regions was strongly diminished in HIV-infected CD4+ cells co-cultivated with CNAR-expressing CD8+ cells. These results demonstrate further that CNAR/CAF has a specific role in regulating HIV transcription and a step during the preinitiation complex assembly appears to be sensitive to CNAR/CAF.

Black men who have sex with men (BMSM) experience among the highest rates of HIV infection in the United States. We conducted a community-based ethnography in New York City to identify the structural and environmental factors that influence BMSMs vulnerability to HIV and their engagement with HIV prevention services. Methods included participant observation at community-based organizations (CBOs) in New York City, in-depth interviews with 31 BMSM, and 17 key informant interviews. Our conceptual framework shows how creating and sustaining safe spaces could be a critical environmental approach to reduce vulnerability to HIV among BMSM. Participant observation, in-depth and key informant interviews revealed that fear and mistrust characterized men's relation to social and public institutions, such as churches, schools, and the police. This fear and mistrust created HIV vulnerability among the BMSM in our sample by challenging engagement with services. Our findings suggest that to be successful, HIV prevention efforts must address these structural and environmental vulnerabilities. Among the CBOs that we studied, "safe spaces" emerged as an important tool for addressing these environmental vulnerabilities. CBOs used safe spaces to provide social support, to address stigma, to prepare men for the workforce, and to foster a sense of community among BMSM. In addition, safe spaces were used for HIV and STI testing and treatment campaigns. Our ethnographic findings suggest that safe spaces represent a promising but so far under-utilized part of HIV prevention infrastructure. Safe spaces seem integral to high impact comprehensive HIV prevention efforts, and may be considered more appropriately as part of HIV capacity-building rather than being nested within program-specific funding structures.

Pulmonary hypertension (PH) is a deadly vascular disease with enigmatic molecular origins. We found that vascular extracellular matrix (ECM) remodeling and stiffening are early and pervasive processes that promote PH. In multiple pulmonary vascular cell types, such ECM stiffening induced the microRNA-130/301 family via activation of the co-transcription factors YAP and TAZ. MicroRNA-130/301 controlled a PPAR?-APOE-LRP8 axis, promoting collagen deposition and LOX-dependent remodeling and further upregulating YAP/TAZ via a mechanoactive feedback loop. In turn, ECM remodeling controlled pulmonary vascular cell crosstalk via such mechanotransduction, modulation of secreted vasoactive effectors, and regulation of associated microRNA pathways. In vivo, pharmacologic inhibition of microRNA-130/301, APOE, or LOX activity ameliorated ECM remodeling and PH. Thus, ECM remodeling, as controlled by the YAP/TAZ-miR-130/301 feedback circuit, is an early PH trigger and offers combinatorial therapeutic targets for this devastating disease.