Qualification: 
Ph.D
indulekhacl@am.amrita.edu

Dr. Indulekha Pillai joins Amrita School of Biotechnology in 2016, from Cedars Sinai Medical Center, Los Angeles, USA. Dr. Pillai finished her post-doctoral research at University of California, Los Angeles (2010-2016), where she worked towards understanding how adult cardiac progenitors are involved in cardiac repair process in response to cardiac injury, using mouse genetic lineage tracing, transgenic and knockout mouse models of disease (I C Pillai et al Cell Stem Cell 2016, Nature 2014; 585-590). Dr. Pillai earned her PhD from Rajiv Gandhi Center for Biotechnology, India (2004-2010). Her PhD work demonstrated the role of notch signalling in the molecular regulation of neuronal sub type specification during embryonic stem cell differentiation (Indulekha et al Cell Mol Life Sci, 2014). In addition, she elucidated the quiescent state of glial progenitors (stromal cells in brain) in homeostatic condition and its activation during adult neurogenesis in rat models of epileptic injury (Indulekha et al Biophys Res Commun 2010). Her current research focuses on cellular and molecular mechanisms of heart injury, fibrosis and regeneration.

Dr. Indulekha Pillai has several International journal publications to her credit and has received many recognitions throughout her academic career. She serves as a reviewer to several international journals in biomedical research. Indulekha Pillai is also a member of the American Heart Association (AHA) and International Society for Stem Cell Research (ISSCR).

Professional Awards/Fellowships Received

  • Ramalingaswami Fellowship from the Department of Biotechnology (DBT), Ministry of Science and Technology, Govt. of India,2017
  • Manuscript, Indulekha Pillai et al, Cardiac Fibroblasts Adopt Osteogenic Fates and Can Be Targeted to Attenuate Pathological Heart Calcification, Cell Stem Cell,2017,20.2,2017 p218–232.e5,selected as Science Magazine Editor’s choice (Science 16 December 2016. Vol 354 issue 6318)
  • Indulekha Pillai et al, paper published in Cell Stem Cell (Indulekha Pillai et al.,2017,20.2,2017 p218–232.e5) selected as Cover story of Cell Stem Cell February 2017 issue.
  • Invited as Moderator and Discussant, Cardiac Fibroblast and Remodelling session, Scientific Sessions, American Heart Association Annual meeting, Dallas, USA,2013  Dr.MR Das Career Award (2011) with gold medal, citation and cash price from Rajiv Gandhi Centre for Biotechnology, India for noted professional achievements as a graduate student.
  • European Union Marie Curie funding to present my work “Notch signalling regulates the expression of Tlx3, a selector gene in excitatory over inhibitory neural fate determination” in 6th International Stem cell school and workshop on hippocampal slice culture, University of Southern Denmark, Denmark,2009
  • International Travel grant, Department of Biotechnology, Govt. of India, for presenting my work, “Hes-1 acts as transcriptional repressor of Tlx3, a selector gene in excitatory over inhibitory neural fate determination” in 39th Annual Meeting of Society for Neuroscience, Chicago, USA, 2009.
  • MSc Biotechnology (2004), First rank, Gold medallist.
  • CSIR JRF and SRF- NET Fellowship (2004 to 2009).
  • Certificate of Merit (2004), Dept. of Biotechnology, University of Kerala for being an outstanding Masters’ student.

Education

YEAR DEGREE/PROGRAM INSTITUTION
2010 PhD Biotechnology Rajiv Gandhi Centre for Biotechnology, India
2004 Masters in Biotechnology Department of Biotechnology, University of Kerala

Selected Presentations

  • “Adult Cardiac Fibroblasts Are Not Terminally Differentiated and Possess Mesenchymal Stem Cell like Properties with Aberrant Differentiation Contributing to Myocardial Calcification” Oral presentation on American Heart Association Scientific Sessions, Dallas, 2013.
  • “Probing the role(s) of the loss of RAN-Binding Protein-2 (RANBP2) in M-cone Photoreceptors and Sub-populations of brain neurons” Poster presented on ARVO 2011, Florida, 2011.
  • “Hes-1 acts as transcriptional repressor of Tlx3, a selector gene in excitatory over inhibitory neural fate determination”. Poster presented on 39th Annual Meeting of Society for Neuroscience, Chicago, 2009.
  • “Notch signaling regulates the expression of Tlx3, a selector gene in excitatory over inhibitory neural fate determination”, Oral and Poster presented on 6th international stem cell school in Regenerative medicine, University of Southern Denmark, Denmark, 2009.
  • “Regulation of Tlx3 gene in neural progenitors: Role of Notch signaling”.Poster presented on International symposium, National Centre for Biological sciences, Bangalore, INDIA, 2008.
  • “Differentiation of Hippocampal progenitors/astrocytes into Excitatory Neurons during Temporal Lobe Epilepsy”. Poster presented on International symposium, XXIII Annual meeting of Indian Academy of Neurosciences, NIMHANS, Bangalore INDIA, 2005.
     

Publications

Publication Type: Journal Article

Year of Publication Publication Type Title

2017

Journal Article

Dr. Indulekha C. L. Pillai, Li, S., Romay, M., Lam, L., Lu, Y., Huang, J., Dillard, N., Zemanova, M., Rubbi, L., Wang, Y., Lee, J., Xia, M., Liang, O., Xie, Y. - H., Pellegrini, M., Lusis, A. J., and Deb, A., “Cardiac Fibroblasts Adopt Osteogenic Fates and Can Be Targeted to Attenuate Pathological Heart Calcification”, Cell Stem Cell, vol. 20, pp. 218 - 232.e5, 2017.[Abstract]


Summary Mammalian tissues calcify with age and injury. Analogous to bone formation, osteogenic cells are thought to be recruited to the affected tissue and induce mineralization. In the heart, calcification of cardiac muscle leads to conduction system disturbances and is one of the most common pathologies underlying heart blocks. However the cell identity and mechanisms contributing to pathological heart muscle calcification remain unknown. Using lineage tracing, murine models of heart calcification and in vivo transplantation assays, we show that cardiac fibroblasts (CFs) adopt an osteoblast cell-like fate and contribute directly to heart muscle calcification. Small-molecule inhibition of ENPP1, an enzyme that is induced upon injury and regulates bone mineralization, significantly attenuated cardiac calcification. Inhibitors of bone mineralization completely prevented ectopic cardiac calcification and improved post injury heart function. Taken together, these findings highlight the plasticity of fibroblasts in contributing to ectopic calcification and identify pharmacological targets for therapeutic development.

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2014

Journal Article

E. Ubil, Duan, J., Dr. Indulekha C. L. Pillai, Rosa-Garrido, M., Wu, Y., Bargiacchi, F., Lu, Y., Stanbouly, S., Huang, J., Rojas, M., Vondriska, T. M., Stefani, E., and Deb, A., “Mesenchymal-endothelial transition contributes to cardiac neovascularization”, Nature, vol. 514, no. 7524, pp. 585-90, 2014.[Abstract]


Endothelial cells contribute to a subset of cardiac fibroblasts by undergoing endothelial-to-mesenchymal transition, but whether cardiac fibroblasts can adopt an endothelial cell fate and directly contribute to neovascularization after cardiac injury is not known. Here, using genetic fate map techniques, we demonstrate that cardiac fibroblasts rapidly adopt an endothelial-cell-like phenotype after acute ischaemic cardiac injury. Fibroblast-derived endothelial cells exhibit anatomical and functional characteristics of native endothelial cells. We show that the transcription factor p53 regulates such a switch in cardiac fibroblast fate. Loss of p53 in cardiac fibroblasts severely decreases the formation of fibroblast-derived endothelial cells, reduces post-infarct vascular density and worsens cardiac function. Conversely, stimulation of the p53 pathway in cardiac fibroblasts augments mesenchymal-to-endothelial transition, enhances vascularity and improves cardiac function. These observations demonstrate that mesenchymal-to-endothelial transition contributes to neovascularization of the injured heart and represents a potential therapeutic target for enhancing cardiac repair.

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2012

Journal Article

Dr. Indulekha C. L. Pillai, Divya, T. Sheela, Divya, M. Sivaraman, Sanalkumar, R., Rasheed, V. Abdul, Dhanesh, S. Bindu, Sebin, A., George, A., and James, J., “Hes-1 regulates the excitatory fate of neural progenitors through modulation of Tlx3 (HOX11L2) expression”, Cell Mol Life Sci, vol. 69, no. 4, pp. 611-27, 2012.[Abstract]


Tlx3 (HOX11L2) is regarded as one of the selector genes in excitatory versus inhibitory fate specification of neurons in distinct regions of the nervous system. Expression of Tlx3 in a post-mitotic immature neuron favors a glutamatergic over GABAergic fate. The factors that regulate Tlx3 have immense importance in the fate specification of glutamatergic neurons. Here, we have shown that Notch target gene, Hes-1, negatively regulates Tlx3 expression, resulting in decreased generation of glutamatergic neurons. Down-regulation of Hes-1 removed the inhibition on Tlx3 promoter, thus promoting glutamatergic differentiation. Promoter-protein interaction studies with truncated/mutated Hes-1 protein suggested that the co-repressor recruitment mediated through WRPW domain of Hes-1 has contributed to the repressive effect. Our results clearly demonstrate a new and unique role for canonical Notch signaling through Hes-1, in neurotransmitter/subtype fate specification of neurons in addition to its known functional role in proliferation/maintenance of neural progenitors.

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2010

Journal Article

R. Sanalkumar, Vidyanand, S., Dr. Indulekha C. L. Pillai, and James, J., “Neuronal vs. Glial Fate of Embryonic Stem Cell-Derived Neural Progenitors (ES-NPs) is Determined by FGF2/EGF During Proliferation”, Journal of Molecular Neuroscience, vol. 42, pp. 17–27, 2010.[Abstract]


Fate-specific differentiation of neural progenitors attracts keen interest in modern medicine due to its application in cell replacement therapy. Though various signaling pathways are involved in maintenance and differentiation of neural progenitors, the mechanism of development of lineage-restricted progenitors from embryonic stem (ES) cells is not clearly understood. Here, we have demonstrated that neuronal vs. glial differentiation potential of ES cell-derived neural progenitors (ES-NPs) are governed by the growth factors, exposed during their proliferation/expansion phase and cannot be significantly altered during differentiation phase. Exposure of ES-NPs to fibroblast growth factor-2 (FGF2) during proliferation triggered the expression of pro-neural genes that are required for neuronal lineage commitment, and upon differentiation, predominantly generated neurons. On the other hand, epidermal growth factor (EGF)-exposed ES-NPs are not committed to neuronal fate due to decreased expression of pro-neural genes. These ES-NPs further generate more glial cells due to expression of glial-restricted factors. Exposure of ES-NPs to the same growth factors during proliferation/expansion and differentiation phase augments the robust differentiation of neurons or glial subtypes. We also demonstrate that, during differentiation, exposure to growth factors other than that in which the ES-NPs were expanded does not significantly alter the fate of ES-NPs. Thus, we conclude that FGF2 and EGF determine the neural vs. glial fate of ES-NPs during proliferation and augment it during differentiation. Further modification of these protocols would help in generating fate-specified neurons for various regenerative therapies. More »»

2010

Journal Article

Dr. Indulekha C. L. Pillai, Sanalkumar, R., Thekkuveettil, A., and James, J., “Seizure induces activation of multiple subtypes of neural progenitors and growth factors in hippocampus with neuronal maturation confined to dentate gyrus”, Biochem Biophys Res Commun, vol. 393, no. 4, pp. 864-71, 2010.[Abstract]


Adult hippocampal neurogenesis is altered in response to different physiological and pathological stimuli. GFAP(+ve)/nestin(+ve) radial glial like Type-1 progenitors are considered to be the resident stem cell population in adult hippocampus. During neurogenesis these Type-1 progenitors matures to GFAP(-ve)/nestin(+ve) Type-2 progenitors and then to Type-3 neuroblasts and finally differentiates into granule cell neurons. In our study, using pilocarpine-induced seizure model, we showed that seizure initiated activation of multiple progenitors in the entire hippocampal area such as DG, CA1 and CA3. Seizure induction resulted in activation of two subtypes of Type-1 progenitors, Type-1a (GFAP(+ve)/nestin(+ve)/BrdU(+ve)) and Type-1b (GFAP(+ve)/nestin(+ve)/BrdU(-ve)). We showed that majority of Type-1b progenitors were undergoing only a transition from a state of dormancy to activated form immediately after seizures rather than proliferating, whereas Type-1a showed maximum proliferation by 3 days post-seizure induction. Type-2 (GFAP(-ve)/nestin(+ve)/BrdU(+ve)) progenitors were few compared to Type-1. Type-3 (DCX(+ve)) progenitors showed increased expression of immature neurons only in DG region by 3 days after seizure induction indicating maturation of progenitors happens only in microenvironment of DG even though progenitors are activated in CA1 and CA3 regions of hippocampus. Also parallel increase in growth factors expression after seizure induction suggests that microenvironmental niche has a profound effect on stimulation of adult neural progenitors.

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2010

Journal Article

R. Sanalkumar, Dr. Indulekha C. L. Pillai, Divya, T. Sheela, Divya, M. Sivaraman, Anto, R. John, Vinod, B., Vidyanand, S., Jagatha, B., Venugopal, S., and James, J., “ATF2 maintains a subset of neural progenitors through CBF1/Notch independent Hes-1 expression and synergistically activates the expression of Hes-1 in Notch-dependent neural progenitors”, J Neurochem, vol. 113, no. 4, pp. 807-18, 2010.[Abstract]


Hes-1 and Hes-5 are downstream effectors of Notch signaling that are known to be involved in different aspects of neural stem cell proliferation and differentiation. Evidence has emerged that Hes-1 expression can be regulated by alternate signaling pathways independent of canonical Notch/CBF1 interaction. This context-dependent differential regulation of Hes-1 expression in neural progenitor gains a lot of importance as it would help in its exponential expansion without the requirement of interaction from neighboring cells during development. Here, we have clearly demonstrated the existence of a population of neural progenitors with Notch/CBF1-independent Hes-1 expression in vitro. Further analysis demonstrated the role of FGF2 in activating Hes-1 expression through the direct binding of ATF2, a JNK downstream target, on Hes-1 promoter. This raises the possibility for the existence of two distinct populations of neural progenitors - one maintained by Hes-1 expression exclusively through Notch-independent mechanism and the other mediating Hes-1 expression through both canonical Notch and FGF2-ATF2 pathway. This alternative pathway will insure a constant expression of Hes-1 even in the absence of canonical Notch intracellular domain-mediated signaling, thereby maintaining a pool of proliferating neural progenitors required during development.

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2009

Journal Article

B. Jagatha, Divya, M. S., Sanalkumar, R., Dr. Indulekha C. L. Pillai, Vidyanand, S., Divya, T. S., Das, A. V., and James, J., “In vitro differentiation of retinal ganglion-like cells from embryonic stem cell derived neural progenitors”, Biochem Biophys Res Commun, vol. 380, no. 2, pp. 230-5, 2009.[Abstract]


ES cells have been reported to serve as an excellent source for obtaining various specialized cell types and could be used in cell replacement therapy. Here, we demonstrate the potential of ES cells to differentiate along retinal ganglion cell (RGC) lineage. FGF2-induced ES cell derived neural progenitors (ES-NPs) were able to generate RGC-like cells in vitro upon differentiation. These cells expressed RGC regulators and markers such as, Ath5, Brn3b, RPF-1, Thy-1 and Islet-1, confirming their potential to differentiate into RGCs. The generation of RGCs from ES-NPs was enhanced with the exposure of FGF2 and Sonic hedgehog (Shh), although Shh treatment alone did not affect RGC differentiation significantly. ES-NPs, after exposure to FGF2, were capable of integrating and differentiating into RGCs in vivo upon transplantation. Thus, our study suggests that ES cells can serve an excellent renewable source for generating RGCs that can be used to treat neurodegenerative diseases like glaucoma.

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