Fallon Durant’s research while affiliated with Harvard University and other places

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Publications (17)


Regeneration and wound healing is variable across vertebrate organisms. Schematic showing representative regenerative abilities in different tissues, disparate time spent in the different stages of wound healing, and variability in cellular response across species. Progressively darker circles mean larger responses as indicated. White circles mean no response, whereas white circles with question marks indicate that the response has not yet been elucidated in the literature.
Wound closure is accomplished through different means in adult versus embryonic mice. A) The first stage of wound healing in adult mice is a hemostatic one, whereby the wound is closed with a fibrin clot. Damaged blood vessels lead to a coagulation of blood in the area of injury, activated platelets migrate to the site and form a sticky plug, and a fibrin network forms a mesh that ultimately creates a clot. B) In embryonic wounds, in lieu of a fibrin clot, at the leading edge of the wound epithelium, cells are connected to one another by actin filaments in a concentric circle around the wound. This cable acts as a contractile “purse string” that closes the wound without need of a coagulative cascade.
The phases of the inflammatory response to wound healing and differences observed in regenerative zebrafish versus non‐regenerative mouse. A) The proinflammatory response to wound healing is dominated by M1 macrophage polarization. In this phase, inflammatory M1 macrophages (orange), T‐effector cells (green), and neutrophils (teal) are recruited to the wound site. Signals released from dying epithelial cells and platelets drive this recruitment, encouraging neutrophils and monocytes to migrate into the area. M1 macrophages differentiate from monocytes, their polarization mediated by neutrophil signals. Macrophages then secrete cytokines that recruit T‐effector cells. B) An M2‐dominant phase begins when macrophages take on M2 polarization phenotypes (light blue) facilitated by T‐regulatory cells (purple). T‐regulatory cells and M2 macrophages secrete factors such as TGF‐β which leads to the differentiation of fibroblasts into myofibroblasts and the secretion of ECM and suppression of inflammatory T‐effector cells. C) The inflammatory response is markedly different in regenerative systems as observed in the zebrafish, D. rerio (dashed lines) than in the mouse M. musculus (solid lines). Comparatively, numbers of neutrophils (blue) and macrophages (red) are lower in zebrafish and peaks in relative cell number take place at earlier time points. The initiation of the transition from M1 to M2 polarization phenotypes in macrophages also take place earlier on (red stars).
Differences between regenerative and non‐regenerative species in proliferation and remodeling stages of wound healing. A) Schematic representation of mammalian prefibrotic cellular proliferation in the adult mouse, M. musculus ≈2–3 days postinjury. Keratinocytes (purple) migrate to the area where the fibrin clot is located and begin to proliferate. These keratinocytes aid in breaking down the fibrin clot and make way for a provisional matrix. Fibroblasts (blue) also proliferate and migrate at this stage and the combined proliferative effort begins the formation of granulation tissue. B) Fibroblasts lay down ECM proteins and produce collagen and fibronectin replacing the fibrin clot with granulation tissue. Fibroblasts differentiate into myofibroblasts (green) which connect to the existing ECM and contract. C) The collagen that is deposited in the area takes on a new, parallel pattern that does not resemble the original basketweave pattern of uninjured tissue. The final result is hypertrophic scarring. D) Schematic representation of the amphibian re‐epithelialization and proliferation response in the axolotl, A. mexicanum ≈12 h postinjury. Keratinocytes crawl over the wound and proliferate after the wound has been covered to make a thick epidermis. Fibroblasts also enter the wound area, proliferate, secrete ECM, and some differentiate into myofibroblasts which similarly contract. E) The wound epidermis continues to thicken, and the clot begins to resolve, leaving behind some residual plasma, blood, and inflammatory cells. F) This ECM then undergoes extensive remodeling during regeneration that renders tissue indistinguishable from uninjured tissue including normal, basketweave collagen distribution. Adapted with permission[²⁶] Copyright 2018, Elsevier.
Regenerative decline and fibrosis after repeat injury in axolotl and zebrafish. A) Experimental overview – age matched siblings were used for repeat amputation experiments whereby control animals were never amputated and experimental animals underwent amputation of both forelimbs. The limbs were allowed at least 9 weeks to regenerate, if they were able, and were then challenged to a repeat amputation in the same amputation plane. This process was repeated until the animal was subject to 5 total rounds of amputation. B) Representative bright‐field photos of the control sibling limb (left) and a limb that failed to regenerate in an experimental animal after repeat amputation (right). C) Cumulative distribution plot of loss of the ability to regenerate beyond the plane of amputation. D) Limb stumps that fail to regenerate exhibit persistent collagen deposition, as observed with Masson's trichrome stain. Intact specimen with no amputations (left) shows normal collagen distribution. Failed regenerates following a repeat same plane amputation (right) showed extensive scar tissue, as evidenced by collagen deposition proximal to the plane of amputation. Middle and lower panels are higher magnification views of the images in the top panels. Brackets indicate epidermis, arrowhead indicates dermis in the control. Scale bars in the top panels are 500 µm and scale bars in the middle and bottom panels are 100 µm. B‐D) Adapted with permission.[¹⁵³] Copyright 2017, The Authors, published by Nature Portfolio. E) Representative schematic of cryoinjury in zebrafish, D. rerio. F) Representative transversal sections of regenerating, cryoinjured zebrafish hearts at 4 days post‐cryoinjury stained with acid Fuchsin and Orange‐G (AFOG) reagent showing myocardium (beige), fibrin (red), and collagen (blue). Multiple cryoinjuries show more collagen deposition. Scale bar = 100 µm. G) Histogram depicting the percentage of collagen observed in the wound area after cryoinjury. Early in regeneration, the amount of collagen deposition is progressive with increasing numbers of cryoinjury exposure. N ≥ 4 hearts, 3 sections per heart. F,G) Adapted with permission.[¹⁵⁴] Copyright 2020, The Authors, published by Springer Nature.

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Finding Solutions for Fibrosis: Understanding the Innate Mechanisms Used by Super‐Regenerator Vertebrates to Combat Scarring
  • Literature Review
  • Full-text available

May 2021

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790 Reads

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25 Citations

Fallon Durant

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Soft tissue fibrosis and cutaneous scarring represent massive clinical burdens to millions of patients per year and the therapeutic options available are currently quite limited. Despite what is known about the process of fibrosis in mammals, novel approaches for combating fibrosis and scarring are necessary. It is hypothesized that scarring has evolved as a solution to maximize healing speed to reduce fluid loss and infection. This hypothesis, however, is complicated by regenerative animals, which have arguably the most remarkable healing abilities and are capable of scar‐free healing. This review explores the differences observed between adult mammalian healing that typically results in fibrosis versus healing in regenerative animals that heal scarlessly. Each stage of wound healing is surveyed in depth from the perspective of many regenerative and fibrotic healers so as to identify the most important molecular and physiological variances along the way to disparate injury repair outcomes. Understanding how these powerful model systems accomplish the feat of scar‐free healing may provide critical therapeutic approaches to the treatment or prevention of fibrosis. Fibrosis is a serious medical problem that remains unresolved in many cases. However, regenerative organisms have evolved to avoid fibrosis and are capable of scar‐free healing. Herein, the physiological and molecular mechanisms behind fibrosis and regenerative wound healing are reviewed and how this knowledge may be applied to solve issues in human health is explored.

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Bistability of somatic pattern memories: stochastic outcomes in bioelectric circuits underlying regeneration

February 2021

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75 Reads

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40 Citations

Nervous systems’ computational abilities are an evolutionary innovation, specializing and speed-optimizing ancient biophysical dynamics. Bioelectric signalling originated in cells' communication with the outside world and with each other, enabling cooperation towards adaptive construction and repair of multicellular bodies. Here, we review the emerging field of developmental bioelectricity, which links the field of basal cognition to state-of-the-art questions in regenerative medicine, synthetic bioengineering and even artificial intelligence. One of the predictions of this view is that regeneration and regulative development can restore correct large-scale anatomies from diverse starting states because, like the brain, they exploit bioelectric encoding of distributed goal states—in this case, pattern memories. We propose a new interpretation of recent stochastic regenerative phenotypes in planaria, by appealing to computational models of memory representation and processing in the brain. Moreover, we discuss novel findings showing that bioelectric changes induced in planaria can be stored in tissue for over a week, thus revealing that somatic bioelectric circuits in vivo can implement a long-term, re-writable memory medium. A consideration of the mechanisms, evolution and functionality of basal cognition makes novel predictions and provides an integrative perspective on the evolution, physiology and biomedicine of information processing in vivo . This article is part of the theme issue ‘Basal cognition: multicellularity, neurons and the cognitive lens’.


Figure 1. Long-term Exposure to BaCl 2 Results in Degeneration of Anterior Tissues and Subsequent Regeneration of Structures That Are Resistant to BaCl 2 (A) Whole D. japonica worms after treatment in 1 mM BaCl 2 . (a) Normal worms before treatment. (b) Within 72 h of exposure to BaCl 2 , the anterior tissues of the planarian degrade and the head deprogresses. This occurs in 83% of worms, SD = 12%. Degeneration occurs through a contraction of tissue at the base of the wound, minimizing tissue loss. (c) After 15 days in BaCl 2 , D. japonica form a blastema and begin to regrow a head. (d) By 37 days of treatment, a new, BaCl 2 -insensitive head has formed and the worm is phenotypically normal. (a'-d') 200x zoomed in images of the anterior portion of the worms shown in (a)-(d). Scale bar 0.5 mm. Results representative of three independent biological replicates, N > 50 for each replicate. (B) (a) D. japonica worm after 35 days of BaCl 2 treatment. This worm has degenerated and regenerated a head and is now insensitive to BaCl 2 . (b) D. japonica worms are then placed in water for 30 days with no obvious morphological effect. (c) However, upon 24 h of a second BaCl 2 treatment, the head degenerates. (a'-c') 200x zoomed in images of the anterior portion of the worms shown in (a)-(c). Scale bar 0.5 mm. Results representative of three independent biological replicates, N > 50 for each replicate.
Figure 2. Possible Mechanism of BaCl 2 -induced Head Degradation Via Excitotoxicity, and Subsequent Adaptation (A) Pathway Studio v10.0 was used to perform pathway analysis of RNA-seq data for (a) anion transport and (b) transmission of nerve impulse, two pathways critical to deprogression and regeneration of the planaria head. Tables S6A and S6B contain details of all of the components listed here. (B) qPCR validation of two transcripts identified as upregulated in the RNA-seq-(a) Dj-TRPMa and (b) Slc2a1. Points represent levels for individual worms normalized to GAPDH. Line indicates median. Unpaired t tests were performed to assess significance, **p < .01, *p < .05, n = 3 for each condition. (C) Proposed regulatory networks detailing (a) normal/untreated state, (b) the main excitotoxicity-related feedback induced by BaCl 2 , and (c) proposed adaptations to BaCl 2 treatment. Red lines with flat endpoints show an inhibitory/ downregulation relationship, whereas blue lines with circular endpoints show an activating/upregulatory relationship. Under normal conditions, K + channels hyperpolarize the cell to regulate membrane excitability and therefore maintain an open state of Ca V channels and upregulate glutamate signaling (a). Ba 2+ is proposed to induce excitotoxicity in neurons by blocking K + channels, leading to significant V mem depolarization, which activates voltage-gated Ca 2+ channels (Ca V )
Figure 3. Visualization of Relative Membrane Potential in WT and BaCl 2 -treated D. japonica Flatworms (A) Voltage-sensitive dye was used to determine pattern of resting potentials in planaria. White arrowheads indicate the anterior of the worm. Images are pseudocolored to allow for ease of visualization of depolarization patterns, but worms were imaged in the same frame so as not to confound data after pseudocoloring, and all image analysis was done using raw un-colored images. (a) Untreated D. japonica flatworm imaged with DiBAC 4 (3) dye. (b) D. japonica flatworm imaged with DiBAC 4 (3) dye after 30 min in BaCl 2 . Scale bars, 0.5 mm. (B) Quantification of average pixel intensities in untreated and BaCl 2 -treated worms. Bars represent mean G SD. Welch's unpaired t test, ***p = 0.00002. See also Figure S1.
Figure 4. Targeting Ion Channels Allows Modulation of Degeneration and Adaptation (A) A variety of drugs targeting ion channels were used to test our excitotoxicity hypothesis. (a and b) D. japonica worm before treatment (a) and after 2 days in water (b). (c and d) Planaria treated with 1 mM BaCl 2 for 0 h (c) show no phenotype, but after 48 h, the head deprogresses (d). (e and f) Planaria in dopamine agonist bromocriptine (0.5 mM) and 1 mM BaCl 2 solution for 0 (e) and 2 days (f). Bromocriptine is able to prevent head degeneration upon exposure to BaCl 2 in 74% of worms (f). (g) exposure to BaCl 2 and calcium-activated chloride channel blocker NPPB (5 mM) has no effect at the time of treatment, but within 2 days (h) NPPB has prevented head degeneration in 84% of worms. (i and j) Calcium-activated chloride channel blocker Niflumic acid (1.24 mM) exposure in combination with BaCl 2 has no effect at 0 days (i) but prevents head degeneration in 92% of worms within 2 days (j). (k and l) L-type calcium channel blocker nicardipine hydrochloride (2.5 mM) treatment in combination with BaCl 2 has no effect at the time of treatment (k) but prevents head degeneration in 78% of worms within 2 days (l). Scale bars, 0.5 mm. (m) Prevalence of head degeneration phenotype with each of the drug treatments listed in (e-l). The overwhelming majority of worms with head degeneration in the BaCl 2 -treated worms are replaced with the majority of worms not experiencing head degeneration when treated with ion channel modulators. (B) Resensitization of worms to BaCl 2 . BaCl 2 -adapted D. japonica worms in (a) water, (b) water with 100 mM AMTB hydrochloride, or (c) water with BaCl 2 do not induce head degeneration in BaCl 2 -adapted worms. (d) However, treatment with AMTB (100 mM) in addition to further treatment with BaCl 2 induced head degeneration within 1.5 h. Scale bars, 0.5 mm. (e) Prevalence of head degeneration phenotypes in BaCl 2 -adapted, BaCl 2 -treated planaria with or without AMTB treatment, as shown in (c) and (d). Treatment with AMTB resulted in a near-complete change from normal heads to fully degenerated heads. See also Figure S2.
Figure S2. Drug treatment alone does not affect planaria, Related to Figure 4. (A) Exposure to Bromocriptine (a,b), NPPB (c,d), Niflumic acid (e,f), or Nicardipine (g,h) for 2 days had no observable effect on D. japonica morphology.
Regenerative Adaptation To Electrochemical Perturbation In Planaria: A Molecular Analysis Of Physiological Plasticity

November 2019

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623 Reads

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26 Citations

iScience

Maya Emmons-Bell

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Fallon Durant

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Angela Tung

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[...]

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Anatomical homeostasis results from dynamic interactions between gene expression, physiology, and the external environment. Owing to its complexity, this cellular and organism-level phenotypic plasticity is still poorly understood. We establish planarian regeneration as a model for acquired tolerance to environments that alter endogenous physiology. Exposure to barium chloride (BaCl2) results in a rapid degeneration of anterior tissue in Dugesia japonica. Remarkably, continued exposure to fresh solution of BaCl2 results in regeneration of heads that are insensitive to BaCl2. RNA-seq revealed transcriptional changes in BaCl2-adapted heads that suggests a model of adaptation to excitotoxicity. Loss-of-function experiments confirmed several predictions: blockage of chloride and calcium channels allowed heads to survive initial BaCl2 exposure, inducing adaptation without prior exposure, whereas blockade of TRPM channels reversed adaptation. Such highly adaptive plasticity may represent an attractive target for biomedical strategies in a wide range of applications beyond its immediate relevance to excitotoxicity preconditioning.


The Role of Early Bioelectric Signals in the Regeneration of Planarian Anterior/Posterior Polarity

February 2019

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146 Reads

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84 Citations

Biophysical Journal

Axial patterning during planarian regeneration relies on a transcriptional circuit that confers distinct positional information on the two ends of an amputated fragment. The earliest known elements of this system begin demarcating differences between anterior and posterior wounds by 6 h postamputation. However, it is still unknown what upstream events break the axial symmetry, allowing a mutual repressor system to establish invariant, distinct biochemical states at the anterior and posterior ends. Here, we show that bioelectric signaling at 3 h is crucial for the formation of proper anterior-posterior polarity in planaria. Briefly manipulating the endogenous bioelectric state by depolarizing the injured tissue during the first 3 h of regeneration alters gene expression by 6 h postamputation and leads to a double-headed phenotype upon regeneration despite confirmed washout of ionophores from tissue. These data reveal a primary functional role for resting membrane potential taking place within the first 3 h after injury and kick-starting the downstream pattern of events that elaborate anatomy over the following 10 days. We propose a simple model of molecular-genetic mechanisms to explain how physiological events taking place immediately after injury regulate the spatial distribution of downstream gene expression and anatomy of regenerating planaria.




Supplementary Material 3

June 2017

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20 Reads

Supplemental Figure 3. Worm colony growth before and after being in space. The number of worms before and after one month in a sealed tube, either while traveling to space and back (circles + dotted lines), or left on Earth (triangles + solid lines), together with number of worms after additional two months on Earth (same starting sample N = same color). Worm colonies which have traveled to space, all have shown slightly reduced rate in colony size growth, compared to their Earth counterparts. (See Supplemental Table 2.) Note that the colony from 10 whole worms left of Earth did not survive the duration of the additional two months on Earth for an unknown reason.





Citations (8)


... 90,172 The identification of EMT responses that are unique to complex tissue regeneration and/or scar-free wound healing in salamanders may inspire therapeutic strategies for overcoming mammalian-specific obstacles to cutaneous and soft-tissue regeneration. [173][174][175] Similarly, studying mammals with exceptional healing properties, such as the African spiny mouse 176 and the MRL strain of the common mouse (Mus musculus), can provide clues for improving mammalian regeneration. ...

Reference:

Putative epithelial–mesenchymal transitions during salamander limb regeneration: Current perspectives and future investigations
Finding Solutions for Fibrosis: Understanding the Innate Mechanisms Used by Super‐Regenerator Vertebrates to Combat Scarring

... One of the key aspects of bioelectric patterns is that in some systems (Xenopus embryo, regenerating planaria, chick embryo), their distribution has been shown to serve as an instructive signal for morphogenesis 30,[90][91][92][93] . Thus, we were very interested in differences in Vmem across the hydra that would correspond to distinct anatomical features. ...

Bistability of somatic pattern memories: stochastic outcomes in bioelectric circuits underlying regeneration

... By placing the cells in a different environment, removing certain developmental constraints rather than by adding new traits to cells, engineers allow them to reset their multicellularity. Cells placed in these unusual situations can identify solutions to new challenges not present in their evolutionary history (Emmons-Bell et al., 2019). Indeed, xenobots showed solutions to problems that are not known yet in life that evolved without the engineering in synthetic morphogenesis. ...

Regenerative Adaptation To Electrochemical Perturbation In Planaria: A Molecular Analysis Of Physiological Plasticity

iScience

... Experimentally, bioelectrical cell states can be instructive for biochemical downstream processes 5,[24][25][26][27][28] . Multicellular potentials convey short-term bioelectrical information to long-term transcriptional processes due to the coupling between the electric potentials and the spatio-temporal distributions of signaling ions (e.g., calcium) and molecules (e.g., serotonin) 5 . ...

The Role of Early Bioelectric Signals in the Regeneration of Planarian Anterior/Posterior Polarity
  • Citing Article
  • February 2019

Biophysical Journal

... Experimentally, bioelectrical cell states can be instructive for biochemical downstream processes 5,[24][25][26][27][28] . Multicellular potentials convey short-term bioelectrical information to long-term transcriptional processes due to the coupling between the electric potentials and the spatio-temporal distributions of signaling ions (e.g., calcium) and molecules (e.g., serotonin) 5 . ...

Long-Term, Stochastic Editing of Regenerative Anatomy via Targeting Endogenous Bioelectric Gradients

Biophysical Journal

... Biology is slowly becoming a matter of engineering. It is now possible to create worms with two heads [21], tadpoles with eyes on their backs that see [22], and biological "xenobots" that perform simple tasks [23]. As biology becomes more tractable, the similarities between biology and human artifice (e.g. ...

Planarian regeneration in space: Persistent anatomical, behavioral, and bacteriological changes induced by space travel

Regeneration

... In a study, AI was utilized to develop insights and patterns from diverse datasets regarding the mechanisms of regeneration in worms. The created model holds the potential to be a valuable asset in advancing the field of TE. 172 Consequently, selecting the optimal combination based on tissue type and patient requirements presents a challenging task. The presence of an intelligent system to integrate experimental data and facilitate appropriate selection becomes imperative. ...

Physiological controls of large-scale patterning in planarian regeneration: a molecular and computational perspective on growth and form

Regeneration

... In planarian flatworms, disruption of gap junction communication during regeneration can lead to double-headed specimens or even worms with characteristics of different planarian species. 9,10 The importance of gap junction connectivity to developmental biology suggests potent applications in synthetic morphology and tissue engineering. ...

Gap Junctional Blockade Stochastically Induces Different Species-Specific Head Anatomies in Genetically Wild-Type Girardia dorotocephala Flatworms
  • Citing Article
  • November 2015

International Journal of Molecular Sciences