NEURO-STEM CELL BIOLOGY LABORATORY
Our lab is currently engaged in developing fate specific differentiation conditions for differentiating embryonic stem (ES) cells into GABAergic neurons and retinal ganglion cells (RGC) for possible therapeutic application in treating refractory temporal lobe epilepsy and Glaucoma, respectively.
Transdifferentiation of Umbilical cord blood derived mesenchymal stem cells into neural lineage, specifically into ocular fate specified cells.
Transplantation of embryonic stem (ES) cells engineered to produce GABA into hippocampus of rats with temporal lobe epilepsy for possible control of seizures
Epilepsy constitutes one of the major public health problems both in developing and developed countries. The factors that determine the development of epilepsy following an initial unprovoked seizure and its refractiveness to antiepileptic drugs (AED) treatment are largely obscure. Among the different subclass of epilepsy, temporal lobe epilepsy (TLE) is the most prevalent seizure disorder in adults. Majority of patients having TLE are refractory to antiepileptic drugs and the only other option for treatment currently available in India is the surgical removal of the focal hippocampus, which has severe side effects like loss of short-term memory. Currently we are looking into the possibility of generating inhibitory GABAergic circuits in hippocampus of rats with refractory temporal lobe epilepsy (TLE) by transplanting transgenic GAD65 expressing embryonic stem (ES) cells into the hippocampus of epileptic rats. Successful generation of GABAergic neurons using GAD65 expressing ES cells in hippocampus will have great implication in effectively treating refractory TLE. Our initial experiments have shown promising results and further studies are being carried out in collaboration with NIMHANS, Bangalore.
Identify the role of Notch and other signaling pathways in formation of new excitatory neural circuits through differentiation of in vivo hippocampal stem cells during temporal lobe epilepsy (TLE)
Delta/Serrate-Notch signaling is an evolutionarily conserved mechanism, utilized by invertebrates and vertebrates alike, to regulate the fate of stem cells/progenitors in a wide variety of tissues. Several studies have suggested that one of the mechanism by which Notch signaling maintains the stem cells/progenitors in an uncommitted state is by suppressing the expression of bHLH transcription factors. For example, the absence of Notch pathway genes, such as Notch-1, CSL or Hes-1 leads to up-regulation of bHLH transcription factors such as NeuroD, Mash-1 and premature neuronal differentiation. The aim of this study is to understand the role of Notch signaling in formation of new excitatory neurons during temporal lobe epilepsy (TLE) since Notch signaling is involved in a context dependent fashion for the maintenance and differentiation of stem cells/progenitors. We have also identified key regulatory pathways involved in deciding the Excitatory (Glutamatergic) Vs Inhibitory (GABAergic) fate of neural progenitors. Currently experiments are being carried out to identify the molecules involved in these fate specifications.
Development of a cell therapy strategy to treat glaucoma using retinal ganglion cells (RGC) generated from embryonic stem cells.
Glaucoma is a heterogeneous group of disorders with a resultant common denominator: optic neuropathy leading eventually to blindness. Known primarily as open angle glaucoma, this is a chronic disease exhibiting progressive loss of retinal ganglion cells and their axons. Elevated intra ocular pressure (IOP) remains the etiological factor towards which major therapeutic efforts are directed, although other approaches are also being considered. We are currently looking into a possible method for increasing the number of RGC by transplanting ES cells that has been induced to differentiate into RGC. Such a strategy will help in replenishing the lost RGC to some extent. Towards this end our laboratory has successfully generated protocol for differentiating ES cells into Retinal Ganglion Cells (Jagatha et.al., 2009, BBRC; 230-235) We are also trying to increase the efficiency of transplantation by growing the differentiating RGC on degradable scaffold material and then transplanting it at specific site of retina. Success of this project will greatly help in treating patients with glaucoma.
Role of Notch signaling in proliferation and maintenance of neural progenitors.
We have identified a Notch independent Hes-1 activation signaling pathway involved in proliferation/maintenance and neuron specific differentiation of ES cell derived neural progenitors. Currently experiments are being carried out to further characterize this signaling pathway.
In addition to the above the following programs are also being carried out in collaboration with other institutes
Development of a biodegradable scaffold for transplanting cells into retina.
Development of neuronal cell lines for drug screening.
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