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Nikolay Ninov Group

Towards in vivo regeneration of beta-cells as a future therapy for T1D

Portrait Nicolay Ninov

© CRTD

The pancreatic β-cells are the key metabolic sensors and effectors for insulin release, which is the only hormone known to lower blood glucose concentrations. Restoring of functional β-cell mass is recognized as a promising therapeutic avenue towards normalizing glycemic control in both type 1 and 2 diabetics, Thus, our research goal is to understand the molecular and cellular events required for pancreatic β-cell regeneration, and apply this knowledge towards the development of cell replacement therapies for diabetes. To advance our knowledge on β-cell regeneration, we focus on identifying the signals that promote the formation of functional β-cells in the body via processes of cell-fate conversion, stem-cell plasticity and integration of the regenerated cells into functional and activity-coordinated networks.

Regeneration of β-cells via cell plasticity: While regeneration is limited in humans, the zebrafish can naturally recover from extreme β cell destruction and hyperglycemia by regenerating new insulin-secreting β cells, which make them an interesting and helpful model organism to uncover the secrets of regeneration. However, the cellular and molecular dynamics underlying this capability were enigmatic. To overcome this knowledge gap, we have applied single-cell transcriptomics and in vivo imaging to build a “β cell regeneration atlas”, spanning the period from β-cell destruction to emergence of new insulin-expressing cells in the pancreatic islets and in doing so, we uncovered one of the secrets behind the outstanding regenerative ability of the zebrafish. We found a previously unknown population of glucose-responsive hybrid cells, which originate from stem-like cells in the pancreatic islet and enable rapid resolution of diabetes in zebrafish (Singh et al., 2022). Our atlas of regeneration provides a rich source of information on the signals that control cell plasticity and restoration of functional islet cells.

Specific questions to be studied: How do the stem-cells sense the loss of β-cells to initiate the process of cell conversion? What is the role of the injury and the arrival of innate and adaptive immune cells in activating this regenerative response? What is the role of the metabolic changes occurring after β-cell loss, including alterations in sugar metabolism, insulin levels and lipids in stimulating the regenerative response? Are the stem cells we found in zebrafish also present in human islets and how can they be harnessed for regenerative purposes in T1D?

Leader β-cells coordinate Ca2+ dynamics across species in vivo: We have identified a critical subpopulation of β-cells present in both the zebrafish and the mouse pancreas, called leader cells, which initiate glucose-stimulated Ca2+ waves and act as islet-pacemakers (Salem et al., 2019) (Video 1). We showed that when leader cells are selectively deactivated or ablated, the response of the whole β-cell population is abrogated, indicating that leader cells initiate insulin release in response to blood sugar. We are exploring the role of leader cells in diabetes progression and islet dysfunction in models of type 1 and type 2 diabetes. To this end, we combine novel Optogenetic systems with Ca2+ imaging in the intact pancreas of the translucent zebrafish. This technology allows to selectively activate or deactivate individual islet cells by shining light on them while studying the effects on the function of the whole network of cells, not only the β-cells but also the α-cells (glucagon-producing) and δ-cells (somatostatin-producing) (→ Figure 1)

Specific questions to be studied: What signaling mechanisms define which β-cells will become leaders and which ones followers? Are leader cells stable in time or do they alternate with non-leader cells? Can leader-cells undergo selective loss of dysfunction under conditions of T2D? Can leader cells regenerate and what are the molecular markers of a leader cell? How do leader cells communicate with the rest of the islet cells to control their activity?

Nikolay Ninov Research: Figure
Figure 1: A zebrafish pancreatic islet in which all three main endocrine cell types are labeled in different colors using different fluorescent proteins: α-cells (blue), β-cells (red) and δ-cells (green). The cell-fate plasticity of α- and δ-cells is essential for rapid regeneration of insulin-producing cells in vivo.
Nikolay Ninov Research: Video 1

Future Projects and Goals

  1. Exploring cell plasticity for tissue regeneration - from zebrafish to human
  2. Defining the role of pacemaker β-cells in establishing functional networks in health and disease
  3. Increasing the resilience of the islet cells to withstand and thrive under stressful conditions, such as immune attack and metabolic pressure

Methodological and Technical Expertise

  • Single-cell genomics
  • Optogenetics and Ca2+ imaging in vivo
  • Drug discovery
  • Zebrafish genetics
  • Diabetes, metabolism and islet biology

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Nikolay Ninov is currently offering PhD positions

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Open Project

CV

since 2020
W2 Professor for Cell Biology and Regeneration of Beta Cells at TU Dresden

since 2013
Group Leader, Center for Regenerative Therapies, Dresden (CRTD), Germany

2009–2013
Postdoctoral Research, University of California, San Francisco USA
Max Planck Institute for Heart and Lung Research Germany

2008–2009
Postdoctoral Research, Department of Cell and Systems Biology, University of Toronto, Canada

2008
Ph.D., University of Barcelona

Selected Publications

Singh SP*, Chawla, P*, Hnatiuk A, Kamel M, Silva LD, Spanjard B, Eski SE, Janjuha S, Olivares P, Kayisoglu O, …, Junker JP, Ninov N
A single-cell atlas of de novo β-cell regeneration reveals the contribution of hybrid β/δ cells to diabetes recovery in zebrafish.
Development 149(2):dev199853 (2022)

Salem V*, Delgadillo L*, Suba K, Georgiadou E, Mousavy NG, Akhtar N, Martin-Alonso A, Gaboriau D, Rothery S, Stylianides T, Carrat G, Pullen T, Pal Singh T, Hodson D, Leclerc I, Shapiro J, Marchetti P, Linford B, Distaso W, Ninov N**, Rutter GA**
Leader β cells coordinate Ca2+ dynamics across pancreatic islets in vivo.
Nature Metabolism 1, 615–629 (2019)
*joint first authors; **corresponding authors

Delgadillo L, Tsakmaki A, Akhtar N, Franklin Z, Konantz J, Bewick GA, Ninov N
Modelling pancreatic β-cell inflammation in zebrafish identifies the natural product wedelolactone for human islet protection.
Disease Models & Mechanisms 2019 12: dmm036004 (2019)

Spanjaard B, Hu B, Mitic N, Olivares-Chauvet P, Janjuha S, Ninov N, Junker JP
Simultaneous lineage tracing and cell type identification using CRISPR/Cas9 induced genetic scars
Nature Biotechnology (2018)

Singh SP, Janjuha S, Hartmann T, Kayısoglu O, Konantz J, Birke S, Murawala P, Alfar EA, Murata K, Eugster A, Tsuji N, Morrissey E, Brand M and Ninov N
Different developmental histories of beta-cells generate functional and proliferative heterogeneity during islet growth
Nat Commun. 8(1):664 (2017)

Contact

Center for Regenerative Therapies Dresden (CRTD)
TU Dresden
Fetscherstraße 105
01307 Dresden