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

Dr. Indulekha Pillai is an Assistant Professor at the School of Biotechnology, Amrita Vishwa Vidyapeetham, India. To establish her research endeavours in India, Dr.Pillai has been awarded the prestigious Ramalingaswami Fellowship from Govt. of India.

She finished her post-doctoral research at the University of California, Los Angeles (2010-2016), and later in Cedars Sinai hospital, Los Angeles, USA. She demonstrated for the first time that adult cardiac fibroblasts cells exhibit stem cell-like plasticity and adopt an osteo-progenitor-like fate during cardiac calcification (I C Pillai et al.Cell Stem Cell 2016, Nature 2014; 585-590). The work has been the cover story of the same issue with an excellent commentary by Dr. Kathryn N Ivey, Senior Investigator, Gladstone Institute of Cardiovascular Disease and University of California San Francisco, California, USA (A Heart of Stone: Cardiac Fibroblasts Turn to Bone in Calcified Hearts, Cell Stem Cell, Vol.20, Issue2, p151-152, February 02, 2017). The research is highlighted by Science Magazine as Editors’ choice(Science16 Dec 2016: Vol.354,Issue 6318,pp.1388). Moreover, the work received extensive media attention and other independent investigators wrote about the work as editorials ("Role of “osteogenic” cardiac fibroblasts in pathological heart calcification" in Stem Cell Investig, volume 4, 26.;"Finding the culprit: who is turning hearts to stone?" in Stem Cell Investig, volume 4, 33).

Dr.Indulekha Pillai’s work as cover story in Cell Stem cell

Cell Stem cell writes: “On the cover: Folk wisdom holds that broken hearts are never quite the same. In time for Valentine's Day, the February 14 American holiday that celebrates romantic love, Pillai et al. (218–232) offer work that challenges this assertion by examining the cell fate changes that occur during pathological heart calcification. They show that after injury cardiac fibroblasts adopt osteogenic cell-like fates that contribute to heart muscle calcification—but fortunately, inhibitors of bone mineralization can attenuate this process and fix the broken heart. The cover image depicts a red heart symbolizing the injured cardiac muscle surrounded by white stones representing the cardiac fibroblasts undergoing osteogenic differentiation.”

Science writes” Electrical impulses propagate through the heart for proper cardiac function. Heart muscle calcification, which can occur with aging, disease, or injury, blocks electrical conduction, resulting in cardiac pump dysfunction and arrhythmias. By tracing cell lineage, Pillai et al. show that cardiac fibroblasts induce this mineralization and take on an osteoblast cell–like fate. Calcification was reduced in mice by administering a small molecule inhibitor that effectively blocks the bone mineralization enzyme ENPP1. Hence, calcification associated with disease or injury may be prevented by targeting ENPP1 to restore cardiac muscle function.”

Dr. Indulekha Pillai earned her Ph.D. from Rajiv Gandhi Center for Biotechnology, India (2004-2010). Her doctoral dissertation addressed how the notch signaling regulates neuronal subtype specification during stem cell differentiation (Indulekha et al. Cell Mol Life Sci, 2014). Besides, she elucidated the quiescence, activation, and differentiation of adult neural progenitors during neurogenesis associated with temporal lobe epileptic injury (Indulekha et al. Biophys Res Commun 2010).

After her doctoral thesis, Dr.Indulekha Pillai worked as a research associate at Duke University, Durham, USA, exploring the role of RanBP2 protein in photoreceptor development and degeneration.

Throughout her career, Dr. Pillai received many awards and recognitions and she serves in the editorial and reviewer boards of different journals in her area of expertise. She is also a member of the American Heart Association (AHA) and the International Society for Stem Cell Research (ISSCR).

Currently, in her lab at Amrita Vishwa Vidyapeetham, Dr.Pillai is exploring the molecular mechanisms modulating regeneration, fibrosis, and calcification in the heart, using induced pluripotent stem cells, bio-engineering principles, and high-content imaging with an ultimate goal to augment the regeneration of the heart.

Qualification:

  • Post-doctoral fellowship: University of California, Los Angeles
  • Post-doctoral fellowship: University of North Carolina, Chapel Hill
  • Ph. D.: Rajiv Gandhi Center for Biotechnology, Department of Biotechnology, Govt. of India
  • M. Sc. Biotechnology: University of Kerala

Awards and Recognitions

  • 2020 - Associate Editor, Frontiers in Genetics
  • 2019 - Member, Board of studies, Immunology, University of Calicut, India
  • 2019 - Editorial Board Member, Frontiers in Cardiovascular Medicine and Systems Medicine
  • 2017 - Ramalingaswami Fellowship from the Department of Biotechnology (DBT), Ministry of Science and Technology, Govt. of India
  • 2016 - Science Magazine highlighted (Science 16 December 2016), 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
  • 2017 - Cover story of Cell Stem Cell, 2017 issue based on Indulekha Pillai et al, Cell Stem Cell (Indulekha Pillai et al.,2017,20.2,2017 p218–232.e5)
  • 2016 - Post-doctoral Scientist, Cedars Sinai Medical Center, Los Angeles, USA, with Dr.Paul Noble, MD and Dianhua Jiang, MD, PhD
  • 2013 – Session chair and Moderator, Cardiac Fibroblast and Remodelling session, Scientific Sessions, American Heart Association, USA
  • 2013 - Post-doctoral fellowship: University of California, Los Angeles, USA with Dr. Arjun Deb, MD
  • 2011 - Post-doctoral Fellowship, University of North Carolina, Chapel Hill, with Dr. Arjun Deb, MD
  • 2011- MR Das Career Award with gold medal and citation, Rajiv Gandhi Centre for Biotechnology, India for noted professional achievements as a graduate student
  • 2010 - Research Fellowship, with Dr. Paulo Ferriera, Duke University, USA
  • 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”, Annual Meeting of Society for Neuroscience, Chicago, USA
  • 2009 - Marie Curie funding (European Union) for 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, University of Southern Denmark, Denmark
  • 2007- Council of Scientific & Industrial Research (CSIR) -Senior Research fellowship
  • 2004 - National Eligibility Test (NET) for Eligibility for Lectureship in Indian Universities
  • 2004 - Council of Scientific & Industrial Research (CSIR) -Junior Research fellowship
  • 2004 - Certificate of Merit, Dept. of Biotechnology, University of Kerala for being an outstanding Masters’ student.
  • 2004 - First rank with Gold medal, MSc Biotechnology, University of Kerala

Publications

Publication Type: Journal Article

Year of Publication Title

2017

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

E. Ubil, JDuan,, Rosa-Garrido, M., Wu, Y., FBargiacchi,, Lu, Y., SStanbouly,, Huang, J., MRojas,, Vondriska, T. M., Stefani, E., Deb, A., and Dr. Indulekha C. L. Pillai, “Mesenchymal–Endothelial Transition Contributes to Cardiac Neovascularisation”, Nature, pp. 585–590, 2014.

2013

C. K, Haque, M., Wang, J., Yu, M., Hao, Y., Qiu, S., Dr. Indulekha C. L. Pillai, Peachey, N., and Ferreira, P. A., “Distinct and Aatypical Intrinsic and Extrinsic Cell Death Pathways between Photoreceptor Cell Types upon Specific Ablation of Ranbp2 in cone Photoreceptors”, PloS Genetics e1003555, vol. 9, no. 6, 2013.

2012

Dr. Indulekha C. L. Pillai, TS, D., MS, D., R, S., VA, R., SB, D., A, S., A, G., and J, J., “Hes-1 Regulates the Excitatory fate of Neural Progenitors through Modulation of Tlx3 (HOX11L2) Expression”, Cellular and Molecular Life Sciences, vol. 69, no. 4, pp. 611-627 , 2012.

2010

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]


<p>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.</p>

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2010

Dr. Indulekha C. L. Pillai, Sanalkumar, R., Thekkuveettil, A., and James, J., “Seizure Induces Activation of Multiple subtypes of Neural Pogenitors 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]


<p>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.</p>

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2010

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 »»

2009

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]


<p>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.</p>

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Selected Presentations

  • “Adult Cardiac Fibroblasts Are Not Terminally Differentiated and Possess Mesenchymal Stem Cell like Properties with Aberrant Differentiation Contributing to Myocardial Calcification” 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” ARVO 2011, Florida, 2011.
  • “Hes-1 acts as transcriptional repressor of Tlx3, a selector gene in excitatory over inhibitory neural fate determination”,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”, 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”, International symposium, National Centre for Biological sciences, Bangalore, INDIA, 2008.
  • “Differentiation of Hippocampal progenitors/astrocytes into Excitatory Neurons during Temporal Lobe Epilepsy”, International symposium, XXIII Annual meeting of Indian Academy of Neurosciences, NIMHANS, Bangalore INDIA, 2005.