Regenerative Medicine seminars

Yun Xia presents macrophage–kidney assembloids that address missing immune and vascular components in stem-cell organoids. Directed differentiation, self-organization, genetic perturbation, xenotransplantation and single-cell analysis reveal immune–epithelial interactions. Macrophages from the same parental cells acquire resident phenotypes; diabetic and polycystic kidney models show context-dependent effects on inflammation, epithelial injury and disease progression. Minoru Takasato addresses kidney organoids’ missing urinary outflow by generating bladder tissue from human pluripotent cells. Stepwise differentiation passes through endoderm, hindgut and cloaca; FGF4 posteriorization and growth-factor screening promote urothelial identity. The resulting sacs contain stratified urothelial cell types, stretch and form a barrier, supporting developmental, disease and future therapeutic studies. Online via Zoom. Tuesday 13 October, 11:00–12:30 SGT (Asia/Singapore). Both talks share this session; individual start times are unspecified. Register through the organizer page. Professional, trainee or student status in stem cells, regenerative medicine or an adjacent field is required; organizer approval and recording restrictions apply.

Astrocytes help sustain neural signaling and tissue stability, but injury and implanted devices cause them to change their functions. Tim O'Shea examines how the extent and timing of this response determine tissue protection, regeneration and implant durability. Limited renewal of adult astrocytes contrasts with the greater proliferation and migration of immature cells in newborn mammals. Around implants, continuing movement, infection and other stimuli can prolong the response and affect device performance. The talk uses astrocyte-specific transcriptomic assays to investigate this reprogramming and considers how to improve repair without sacrificing normal astrocyte functions. It also presents biomaterial and cell-transplant approaches being studied in preclinical stroke, spinal cord injury and implant-response models.

UCL Department of Neuroinflammation Seminar by Professor Emad Moeendarbary (Professor of Cell Mechanics and Mechanobiology, UCL Mechanical Engineering) on how biophysical factors such as substrate stiffness and axon geometry regulate oligodendrocyte behavior and myelin formation, presenting the AxoMetic in vitro myelination platform for discovery of remyelinating therapies.

Neurotrophins (NGF, BDNF, NT-3) are endogenous growth factors that exert neuroprotective effects by preventing neuronal death and promoting neurogenesis. They act by binding to their respective high-affinity, pro-survival receptors TrkA, TrkB or TrkC, as well as to p75NTR death receptor. While these molecules have been shown to significantly slow or prevent neurodegeneration, their reduced bioavailability and inability to penetrate the blood-brain-barrier limit their use as potential therapeutics. To bypass these limitations, our research team has developed and patented small-sized, lipophilic compounds which selectively resemble neurotrophins’ effects, presenting preferable pharmacological properties and promoting neuroprotection and repair against neurodegeneration. In addition, the combination of these molecules with 3D cultured human neuronal cells, and their targeted delivery in the brain ventricles through soft robotic systems, could offer novel therapeutic approaches against neurodegenerative diseases and brain trauma.

Current disease-modifying therapies in multiple sclerosis are all focused on suppressing the inflammatory phase of the disease. This has been extremely successful, and it is doubtful that significantly more efficacious anti-inflammatory treatments will be found. However, it remains the case that people with relapsing-remitting multiple sclerosis acquire disability on treatment, and enter the secondary progressive phase. I argue that we now need treatments that prevent neuronal degeneration. The most promising approach is to prevent axons degenerating by remyelination. Since the discovery that the adult brain contains stem cells which can remyelinate, the problem now is how to promote endogenous remyelination, and how to know when we have achieved this! We have successfully identified one drug which promotes remyelination but unfortunately it is too toxic for use in the clinic. So the hunt continues.

Our goal is to understand why myelin repair fails in multiple sclerosis and to develop regenerative medicines for the nervous system. A central obstacle for progress in this area has been the complex biology underlying the response to CNS injury. Acute CNS damage is followed by a multicellular response that encompasses different cell types and spans different scales. Currently, we do not understand which factors determines lesion recovery. Failure of inflammation to resolve is a key underlying reason of poor regeneration, and one focus is therefore on the biology of microglia during de- and remyelination, and their cross talk to other cells, in particular oligodendrocytes and the progenitor cells. In addition, we are exploring the link between lipid metabolism and inflammation, and its role in the regulation of regeneration. I will report about our recent progress in our understanding of how microglia promote regeneration in the CNS.

Inhibitory interneurons govern the sparse activation of principal cells that permits appropriate behaviors, but they among the most vulnerable to brain damage. Our recent work has demonstrated important roles for inhibitory neurons in disorders of brain development, injury and epilepsy. These studies have motivated our ongoing efforts to understand how these cells operate at the synaptic, circuit and behavioral levels and in designing new technologies targeting specific populations of interneurons for therapy. I will discuss our recent efforts examining the role of interneurons in traumatic brain injury and in designing cell transplantation strategies - based on the generation of new inhibitory interneurons - that enable precise manipulation of inhibitory circuits in the injured brain. I will also discuss our ongoing efforts using monosynaptic virus tracing and whole-brain clearing methods to generate brain-wide maps of inhibitory circuits in the rodent brain. By comprehensively mapping the wiring of individual cell types on a global scale, we have uncovered a fundamental strategy to sustain and optimize inhibition following traumatic brain injury that involves spatial reorganization of local and long-range inputs to inhibitory neurons. These recent findings suggest that brain damage, even when focally restricted, likely has a far broader affect on brain-wide neural function than previously appreciated.

My research uses electrophysiological techniques to evaluate normal retinal function, dysfunction caused by blinding retinal diseases and the restoration of function using a variety of therapeutic strategies. We can use our understanding or normal retinal function and disease-related changes to construct optimal therapeutic strategies and evaluate how they ameliorate the effects of disease. Retinitis pigmentosa (RP) is a family of blinding eye diseases caused by photoreceptor degeneration. The absence of the cells that for this primary signal leads to blindness. My interest in RP involves the evaluation of therapies to restore vision: replacing degenerated photoreceptors either with: (1) new stem or other embryonic cells, manipulated to become photoreceptors or (2) prosthetics devices that replace the photoreceptor signal with an electronic signal to light. Glaucoma is caused by increased intraocular pressure and leads to ganglion cell death, which eliminates the link between the retinal output and central visual processing. We are parsing out of the effects of increased intraocular pressure and aging on ganglion cells. Congenital Stationary Night Blindness (CSNB) is a family of diseases in which signaling is eliminated between rod photoreceptors and their postsynaptic targets, rod bipolar cells. This deafferents the retinal circuit that is responsible for vision under dim lighting. My interest in CSNB involves understanding the basic interplay between excitation and inhibition in the retinal circuit and its normal development. Because of the targeted nature of this disease, we are hopeful that a gene therapy approach can be developed to restore night vision. My work utilizes rodent disease models whose mutations mimic those found in human patients. While molecular manipulation of rodents is a fairly common approach, we have recently developed a mutant NIH miniature swine model of a common form of autosomal dominant RP (Pro23His rhodopsin mutation) in collaboration with the National Swine Resource Research Center at University of Missouri. More genetically modified mini-swine models are in the pipeline to examine other retinal diseases.

Almost everybody that has seen neurons under a microscope for the first time is fascinated by their beauty and their complex shape. Early on during development, however, there are hardly any signs of their future complexity, but the neurons look round and simple. How do neurons develop their sophisticated structure? How do they initially generate domains that later have distinct function within neuronal circuits, such as the axon? And, can a better understanding of the underlying developmental mechanisms help us in pathological conditions, such as a spinal cord injury, to induce axons to regenerate? Here, I will talk about the cytoskeleton as a driving force for neuronal polarization. We will then explore how cytoskeletal changes help to reactivate the growth program of injured CNS axons to elicit axon regeneration after a spinal cord injury. Finally, we will discuss whether axon growth and synapse formation may be processes in neurons that might exclude each other. Following this developmental hypothesis, it will help us to generate a novel perspective on regeneration failure in the adult CNS, and how we can overcome this failure to induce axon regeneration. Thus, this talk will describe how we can exploit developmental mechanisms to induce axon regeneration after a spinal cord injury.

The CNS is responsive to an ever-changing environment. Until recently, studies of neural plasticity focused almost exclusively on functional and structural changes of neuronal synapses. In recent years, myelin plasticity has emerged as a potential modulator of neural networks. Myelination of previously unmyelinated axons, and changes in the structure on already-myelinated axons, can have large effects on network function. The heterogeneity of the extent of how axons in the CNS are myelinated offers diverse scope for dynamic myelin changes to fine-tune neural circuits. The traditionally held view of myelin as a passive insulator of axons is now changing to one of lifelong changes in myelin, modulated by neuronal activity and experience. Myelin, produced by oligodendrocytes (OLs), is essential for normal brain function, as it provides fast signal transmission, promotes synchronization of neuronal signals and helps to maintain neuronal function. OLs differentiate from oligodendrocyte precursor cells (OPCs), which are distributed throughout the adult brain, and myelination continues into late adulthood. OPCs can sense neuronal activity as they receive synaptic inputs from neurons and express voltage-gated ion channels and neurotransmitter receptors, and differentiate into myelinating OLs in response to changes in neuronal activity. This lecture will explore to what extent myelin plasticity occurs in adult animals, whether myelin changes occur in non-motor learning tasks, especially in learning and memory, and questions whether myelin plasticity and myelin regeneration are two sides of the same coin.

Dr. Gupta is carrying out his post doctoral studies in the Buter Laboratory in UCLA. He is applying his his knowledge of embryology to stem cells for developing regenerative therapies to treat spinal cord injuries. In this talk, he will discuss how understanding the logic for spinal cord development led us to derive diverse sensory neuronal classes from embryonic stem cells. The spinal sensory neurons enableus to perceive our environment through modalities that are lost in spinal injury patients. These ESC derived senory neurons can help regain sensation in spina cord injury patients through regenerative therapies.

There are currently no approved therapies to slow down the accumulation of neurological disability that occurs independently of relapses in multiple sclerosis (MS). International agencies are engaging to expedite the development of novel strategies capable of modifying disease progression, abrogating persistent CNS inflammation, and support degenerating axons in people with progressive MS. Understanding why regeneration fails in the progressive MS brain and developing new regenerative approaches is a key priority for the Pluchino Lab. In particular, we aim to elucidate how the immune system, in particular its cells called myeloid cells, affects brain structure and function under normal healthy conditions and in disease. Our objective is to find how myeloid cells communicate with the central nervous system and affect tissue healing and functional recovery by stimulating mechanisms of brain plasticity mechanisms such as the generation of new nerve cells and the reduction of scar formation. Applying combination of state-of-the-art omic technologies, and molecular approaches to study murine and human disease models of inflammation and neurodegeneration, we aim to develop experimental molecular medicines, including those with stem cells and gene therapy vectors, which slow down the accumulation of irreversible disabilities and improve functional recovery after progressive multiple sclerosis, stroke and traumatic injuries. By understanding the mechanisms of intercellular (neuro-immune) signalling, diseases of the brain and spinal cord may be treated more effectively, and significant neuroprotection may be achieved with new tailored molecular therapeutics.

A key question for basic biology and regenerative medicine concerns the way in which evolution exploits physics toward adaptive form and function. While genomes specify the molecular hardware of cells, what algorithms enable cellular collectives to reliably build specific, complex, target morphologies? Our lab studies the way in which all cells, not just neurons, communicate as electrical networks that enable scaling of single-cell properties into collective intelligences that solve problems in anatomical feature space. By learning to read, interpret, and write bioelectrical information in vivo, we have identified some novel controls of growth and form that enable incredible plasticity and robustness in anatomical homeostasis. In this talk, I will describe the fundamental knowledge gaps with respect to anatomical plasticity and pattern control beyond emergence, and discuss our efforts to understand large-scale morphological control circuits. I will show examples in embryogenesis, regeneration, cancer, and synthetic living machines. I will also discuss the implications of this work for not only regenerative medicine, but also for fundamental understanding of the origin of bodyplans and the relationship between genomes and functional anatomy.

Traumatic injury in the nervous system leads to devastating consequences such as paralysis. The regenerative capacity of the nervous system is limited in adulthood. In this talk, Dr. Anindya would be sharing how the simple nematode C. elegans with its known connectome can inform us about the biology of nervous system repair.

In order to re-install neurogenesis after loss of neurons upon injury or neurodegeneration, we need to understand the basic principles of neurogenesis. I will first discuss about our discovery of a novel centrosome protein (Camargo et al., 2019) and discuss unpublished work about the great diversity of interphase centrosome proteomes and their relevance for neurodevelopmental disorders. I would then present work on a master regulator of neural stem cell amplification and brain folding (Stahl et al., 2013; Esgleas et al., 2020) to proceed presenting data on utilizing some of these factors for turning astrocytes into neurons. I will present data on the critical role of mitochondria in this conversion process (Gascon et al., 2016, Russo et al., 2020) and how it regulates the speed of conversion also showing unpublished data. If time permits I may touch on recent progress in in vivo reprogramming (Mattugini et al., 2019). Taken together, these data highlight the surprising specificity and importance of organelle diversity from centrosome, nucleolus and mitochondria as key regulators in development and reprogramming.