Regenerative agriculture | EPFL Graph Search

Regenerative agriculture is a conservation and rehabilitation approach to food and farming systems. It focuses on topsoil regeneration, increasing biodiversity, improving the water cycle, enhancing ecosystem services, supporting biosequestration, increasing resilience to climate change, and strengthening the health and vitality of farm soil. Regenerative agriculture is not a specific practice itself. Rather, proponents of regenerative agriculture use a variety of sustainable agriculture techniques in combination. Practices include recycling as much farm waste as possible and adding composted material from sources outside the farm. Regenerative agriculture on small farms and gardens is often based on philosophies like permaculture, agroecology, agroforestry, restoration ecology, keyline design, and holistic management. Large farms are also increasingly adopting such techniques, and often use "no-till" and/or "reduced till" practices. As soil health improves, input requirements may decrease, and crop yields may increase as soils are more resilient against extreme weather and harbor fewer pests and pathogens. Regenerative agriculture mitigates climate change through carbon dioxide removal, i.e. it draws carbon from the atmosphere and sequesters it. Regenerative agriculture is based on various agricultural and ecological practices, with a particular emphasis on minimal soil disturbance and the practice of composting. Maynard Murray had similar ideas, using sea minerals. His work led to innovations in no-till practices, such as slash and mulch in tropical regions. Sheet mulching is a regenerative agriculture practice that smothers weeds and adds nutrients to the soil below. In the early 1980s, the Rodale Institute began using the term ‘regenerative agriculture’. Rodale Publishing formed the Regenerative Agriculture Association, which began publishing regenerative agriculture books in 1987 and 1988. By marching forward under the banner of sustainability we are, in effect, continuing to hamper ourselves by not accepting a challenging enough goal.

The role of sensorimotor afferent feedback in mediating functional recovery after spinal cord injury

Kay Alexander Bartholdi

Spinal cord injury (SCI) leads to permanent deficits in sensory and motor function due to the physical disruption of descending and ascending pathways. As a consequence, spinal circuits below the level of lesion remain in an intact, but inactive state. A number of studies have shown that epidural electrical stimulation (EES) of the lumbar spinal cord can reactivate these spinal circuits after SCI. EES reversed paralysis of lower limbs in rodent and primate models of SCI as well as in a number of clinical case studies. However, although the positive effects of EES have been documented, little is known about the neural circuits through which EES enables motor pattern formation after SCI. In the first part of this thesis, we examined the neural circuits activated by EES. In the past, modeling experiments highlighted a pivotal role for large-diameter, myelinated afferent circuits in mediating the facilitating effects of EES after SCI. Using calcium imaging and chemogenetic inactivation experiments, we confirmed that EES primarily recruits proprioceptive and low-threshold mechanoreceptor feedback circuits. We next sought to exploit this knowledge to specifically enhance the effects of EES. We found that alpha2a receptors are prominently expressed on proprioceptive afferent neurons in DRGs, whereas alpha2c receptors are located on low-threshold mechanoreceptor interneurons in the dorsal spinal horn. Based on this knowledge, we built a computational model that identified beneficial and detrimental interactions between EES and noradrenergic circuits. This understanding guided the design of a circuit-specific, electrochemical neuromodulation that specifically gated the effects of EES towards proprioceptive feedback circuits and re-established locomotion in paralyzed mice and rats. The second part of this thesis uncovers the impact of movement on sensory afferent pathways. For this, mice were exposed to environmental enrichment (EE) or standard housing (SH). We found that EE primed sensory dorsal root ganglia neurons, inducing a lasting increase in their regenerative potential after SCI. This EE-mediated increase in regenerative potential was confined to proprioceptive afferent neurons and characterized through increased calcium signalling and CBP-dependent histone acetylation which is associated with enhanced gene expression. In a next step, we mimicked the exposure to EE using pharmacology. The pharmacological activation of CBP after injury enhanced axonal growth of proprioceptive afferent fibers and enhanced the recovery of sensory and motor functions. Here, we provide direct and conclusive experimental evidence for the mechanistic understanding of EES and EE and how they mediate functional recovery after SCI. Based on this knowledge, we identified specific receptors and epigenetic mechanisms for pharmacological modulation. Our findings demonstrate the importance of large-diameter afferent fibers in mediating functional recovery and will be important in establishing a framework for the design of targeted neuromodulation therapies after SCI in human patients.

EPFL2019

Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models

Grégoire Courtine, Quentin Barraud, Claudia Kathe, Thomas Haynes Hutson, Kay Alexander Bartholdi

After a spinal cord injury, axons fail to regenerate in the adult mammalian central nervous system, leading to permanent deficits in sensory and motor functions. Increasing neuronal activity after an injury using electrical stimulation or rehabilitation can enhance neuronal plasticity and result in some degree of recovery; however, the underlying mechanisms remain poorly understood. We found that placing mice in an enriched environment before an injury enhanced the activity of proprioceptive dorsal root ganglion neurons, leading to a lasting increase in their regenerative potential. This effect was dependent on Creb-binding protein (Cbp)-mediated histone acetylation, which increased the expression of genes associated with the regenerative program. Intraperitoneal delivery of a small-molecule activator of Cbp at clinically relevant times promoted regeneration and sprouting of sensory and motor axons, as well as recovery of sensory and motor functions in both the mouse and rat model of spinal cord injury. Our findings showed that the increased regenerative capacity induced by enhancing neuronal activity is mediated by epigenetic reprogramming in rodent models of spinal cord injury. Understanding the mechanisms underlying activity-dependent neuronal plasticity led to the identification of potential molecular targets for improving recovery after spinal cord injury.

AMER ASSOC ADVANCEMENT SCIENCE2019

Engineering the Extra Domain A of fibronectin as a vaccine adjuvant and study of its role in tissue regeneration

Ziad Julier

The extracellular matrix (ECM) protein fibronectin (FN) is a remarkably multifaceted molecule, including numerous fibronectin type III (FNIII) repeats carrying out different functions, which despite being extensively studied for over thirty years still presents certain functions that remain incompletely elucidated. The alternatively spliced FN variant containing the extra domain A (FNIII EDA), located between FNIII 11 and FNIII 12, is expressed in sites of injury, chronic inflammation, and solid tumors. Although its function is not well understood, FNIII EDA is known to agonize Toll-like receptor 4 (TLR4) and appears to be involved in the progression of different skin diseases while studies also suggest that FNIII EDA is involved in tissue repair. The aim of this thesis is thus to better understand some of the immunological and regenerative functions of FNIII EDA and to translate these findings to develop new vaccination strategies based on endogenous proteins. One important task in vaccinology is to develop delivery strategies by which to present antigen, along TLR agonists, so as to induce a desirable adaptive immune response. The use of TLR agonists is associated with sometimes severe constraints and concerns about safety, causing inflammatory responses. Thus, the development of safe and effective vaccines with fewer side effects is a strong need and requires the development of new adjuvants with a correct balance between a strong activation of the immune system and a low toxicity for the patient. Here, by producing various FN fragments containing FNIII EDA, we show that the immunological activity of FNIII EDA depends on its local intramolecular context within the FN chain. N-terminal extension of the isolated FNIII EDA with its neighboring FNIII repeats enhanced its activity in agonizing TLR4, while C-terminal extension abrogated it. In addition, we reveal that an elastase 2 cleavage site is present between FNIII EDA and FNIII 12. Moreover, as FNIII EDA is naturally present within the ECM, we incorporated FNIII EDA bound in a fibrin matrix to mimic the in vivo situation and create an adjuvant-rich microenvironment. Such matrices were shown to induce functional cytotoxic CD8+ T cell responses in two murine cancer models. Furthermore, combinations of specific TLR-agonists have the ability to synergize to induce immune responses that are greater than the sum of their individual effect. Hence, we demonstrate that combination of the TLR9 agonist CpG with FNIII EDA synergizes to induce an efficient immune response while keeping the dose of the toxic CpG at a minimum. Here, the combination of both adjuvants induced a potent immune response sufficient to slow down tumor growth in a murine tumor model as well as to break immune tolerance to eradicate circulating hepatitis B virus (HBV) in a transgenic HBV mouse model. Finally in the last part of this thesis we revealed that FNIII EDA is a growth factor binding domain of FN, with a strong affinity for the platelet-derived growth factor-AA (PDGF-AA). We also demonstrated that FNIII EDA and PDGF-AA have together the ability to enhance fibroblasts proliferation and differentiation into myofibroblasts. In addition, we explored the effects of fibrin matrices functionalized with variants of FNIII EDA on wound closure.

EPFL2016