Current projects in the lab focus on stem cell biology mainly in the context of Aging and Parkinson’s Disease (PD), using rodent and human systems.
Stem cells and Aging
Of major interest In the lab is the question how stem cells survive and function in an aging brain environment - a crucial issue that needs to be understood if stem cell-based therapies for Parkinson’s disease, and other age-related neural disorders, are to be developed. In this respect, it is known that the aging brain environment negatively impacts the regenerative function of endogenous neural stem cells present in two specialized brain niches, namely the subventricular zone (SVZ) and dentate gyrus (DG) of the hippocampus. Nevertheless, neural stem cell regeneration, although subdued, does persist in the aging brain suggesting that it can be plausibly harnessed towards therapeutic ends. The aim of our studies is to carefully delineate the parameters and mechanisms of the age-related decline in NSC function, and use this information to develop methods to enhance the plasticity of endogenous as well as transplanted neural stem cells in the aging brain.
Recently we have discovered a novel role for the redox-sensitive transcription factor Nrf2 in neural stem cell aging, and are pursuing the mechanisms underlying the molecule’s effects, and also exploring it as a target to improve neural stem cell function with age. Please check out our recent publications on this topic!
(Corenblum et al., 2016; Aging Cell; Madhavan L, 2016, Biochemical Soc.Transactions).
Induced pluripotent stem (iPS) cells for modeling PD and developing cell-based therapeutics
A crucial factor limiting scientific progress in understanding PD pathogenesis has been the lack of robust research models, particularly in the form of relevant neural tissue from PD patient populations. In this context, our lab has created human induced pluripotent stem cell (iPSC) lines reprogramed from skin fibroblasts of sporadic PD patients. These skin fibroblasts and iPSCs are currently being used in the lab as powerful patient- and disease- specific systems to generate disease relevant neural cell-types and investigate mechanisms contributing to the development of PD. A future goal is to develop clinically usable iPS-derived cells for cell therapy in neurodegenerative disorder patients. We have two manuscripts, one just accepted and one in preparation on this topic. Please stay tuned!
(Corenblum and Madhavan, 2016, JOVE; Teves et al., 2016)
Graft host-interactions after stem cell transplantation
The basis of stem cell mediated plasticity and repair lies in their interactions with their ‘niche’ or local environment in the brain. A series of our work has shown that such interactions between grafted stem cells and host cells can lead to reparative, regenerative, and protective effects in Parkinsonian animal models, especially when the cells are implanted during early stages of PD pathology. One important goal in the lab is to further understand the tenets of such powerful graft and host signaling which we see as key in realizing the therapeutic purpose of stem cells. In this context, we have recently identified sonic hedgehog as a key factor support graft-host communication. In addition to a major focus, which is on neural stem cells, more recently we have become interested in examining the dynamics of such graft-host signaling using more clinically attractive stem cells such as cord-blood derived stem cells. Please check out our recent publications on this topic!
(Madhavan et al., 2016, PLOSOne; Corenblum et al., 2016, Regen Med)
Dynamic imaging of stem cells in vivo
Developing successful stem cell therapies will in part require methods to safely monitor the location, distribution, and long-term viability of these cells, in a noninvasive manner across time, in brain tissues of patients. In this context, we are interested in technologies which will allow the in vivo tracking of transplanted as well as endogenous stem cells. Recently we have investigated the potential of a specific magnetic resonance imaging (MRI) based methodology to monitor implanted neural stem cells in ‘real time’ in the brains of adult rats. Please read our publication on this topic!
(Umashankar et al., 2016, International Journal of Nanomedicine)