The field of regenerative medicine has focused on the use of biochemical factors, such as cytokines and morphogens, to modulate stem cell behavior and tissue outcomes. In contrast, endogenous bioelectric signals (steady-state resting potential or Vmem) have long been identified as a key factor in tissue development and tissue repair, but have only received very limited attention towards the field of regenerative medicine. In our current grant we have made major progress in elucidating the role of Vmem in modulating stem cell behavior and tissue repair as a transformative application for regenerative medicine. In this renewal application, we plan to gain further mechanistic insight into signaling by changes of Vmem in non-neural cells as well as into the self-organizing properties of Vmem-regulatory networks to embed desired Vmem patterns into engineered tissues to direct tissue function. Our goal is to advance our understanding and implementation of bioelectric signaling as a tool for regenerative medicine applications. Our hypothesis is that a better understanding of bioelectric signaling on the molecular and cellular levels has the potential to impact tissue engineering, stem cell therapies, and tissue regeneration. In our two proposed aims we will:
(Aim 1) dig deeper into the mechanisms governing how voltage signals are transduced into cellular responses, and (Aim 2) we will explore how to incorporate bioelectric patterning in 2D and 3D tissue models by specifying Vmem with high temporal and spatial control using optogenetics tools and patterned drug delivery. Through these Aims, we will address our hypothesis from two angles: the mechanistic, molecular basis of voltage signaling, and the broad, tissue-wide patterning application for which voltage signaling may be utilized. As in the current grant, this i a team approach with two PIs with complementary and synergistic skills, David Kaplan (Biomedical Engineering) with a focus on stem cells and tissue formation in vitro, and Michael Levin (Biology) with a focus on molecular tools for Vmem control and tissue development. The team has made substantive progress in the first 3-plus years on the current grant. Major impact to the field of regenerative medicine is anticipated with the plans proposed in this renewal program by harnessing bioelectric signaling. !

Public Health Relevance

The proposed studies would bring the field of biophysical signaling into the mainstream as a practical and defined approach to tissue pattern control and regeneration. This approach would impact wound healing treatments as well as chronic regenerative strategies that aim to restore tissue and organ functions. Further, such strategies can also impact broader stem cell issues such as maintenance of stemness during cell propagation, improved approaches to cell-specific differentiation, and more insight into lineage specification during cell transdifferentiation.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wang, Fei
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Tufts University
Engineering (All Types)
Biomed Engr/Col Engr/Engr Sta
United States
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Levin, Michael; Pietak, Alexis M; Bischof, Johanna (2018) Planarian regeneration as a model of anatomical homeostasis: Recent progress in biophysical and computational approaches. Semin Cell Dev Biol :
Herrera-Rincon, Celia; Golding, Annie S; Moran, Kristine M et al. (2018) Brief Local Application of Progesterone via a Wearable Bioreactor Induces Long-Term Regenerative Response in Adult Xenopus Hindlimb. Cell Rep 25:1593-1609.e7
Pai, Vaibhav P; Pietak, Alexis; Willocq, Valerie et al. (2018) HCN2 Rescues brain defects by enforcing endogenous voltage pre-patterns. Nat Commun 9:998
McLaughlin, Kelly A; Levin, Michael (2018) Bioelectric signaling in regeneration: Mechanisms of ionic controls of growth and form. Dev Biol 433:177-189
Thurber, Amy E; Nelson, Michaela; Frost, Crystal L et al. (2017) IK channel activation increases tumor growth and induces differential behavioral responses in two breast epithelial cell lines. Oncotarget 8:42382-42397
Grasman, Jonathan M; Kaplan, David L (2017) Human endothelial cells secrete neurotropic factors to direct axonal growth of peripheral nerves. Sci Rep 7:4092
Herrera-Rincon, Celia; Pai, Vaibhav P; Moran, Kristine M et al. (2017) The brain is required for normal muscle and nerve patterning during early Xenopus development. Nat Commun 8:587
Mathews, Juanita; Levin, Michael (2017) Gap junctional signaling in pattern regulation: Physiological network connectivity instructs growth and form. Dev Neurobiol 77:643-673
Pietak, Alexis; Levin, Michael (2016) Exploring Instructive Physiological Signaling with the Bioelectric Tissue Simulation Engine. Front Bioeng Biotechnol 4:55
Durant, Fallon; Lobo, Daniel; Hammelman, Jennifer et al. (2016) Physiological controls of large-scale patterning in planarian regeneration: a molecular and computational perspective on growth and form. Regeneration (Oxf) 3:78-102

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