The developmental plasticity of the pancreas has been extensively studied. Leaving aside the ongoing debate about the relative contribution of neogenesis and endocrine cell self-duplication to islet regeneration in mice, the notion that progenitor cells can regenerate islets has been recently substantiated in human models. That this potential is intrinsic is evidenced by the observation that sorted human progenitors recapitulate complex, anatomically accurate pancreatic structures when transplanted into immunodeficient mice. An already substantial body of work also points at tissue stress and inflammation as critical drivers of this regenerative program –which would explain why ductal remodeling and intraductal endocrine cells are commonly observed during pancreatic injury and diabetes but seldom in the healthy organ. We have additionally established that BMP signaling stimulation accelerates this process, both in vitro and in vivo, opening the door to pharmacological approaches to induce β-cell regeneration in situ.
Still, there remain many open questions. To put it plainly, nobody has ever seen regeneration unfold in real time in alive pancreas. We rely mostly on in vitro models (which show regeneration but may not accurately represent in vivo phenomena), inferences from static data (e.g., β-cells in apposition to ducts following pancreatic injury or pseudotime cell trajectory predictions), or the post-hoc interpretation of lineage tracing observations (which are often contradictory owing to technical and biological reasons). Our team has gone one step further by dissecting the process dynamically at the single-cell level using long-term cultured mouse and human pancreatic slices. However, for all the might of this organotypic model compared to other alternatives, they remain ultimately an in vitro system –and, as such, weighed down by caveats (chiefly lack of blood circulation) common to all such settings. These technological bottlenecks have led to a situation in which every finding can be either qualified or disputed based on the perceived limitations of any given model or the interpretation of their output, prompting intense academic debates about the nature and extent of pancreatic regeneration.
We hypothesize that the transplantation of human pancreatic slices or sorted progenitor cells into the anterior chamber of the eye (ACE) of immunodeficient murine hosts will address the above shortcomings by enabling the longitudinal study of human progenitor cell potency and islet regeneration over many months. The efficient engraftment of human pancreatic tissue in this location affords us the possibility to delve into a living, functional, and fully vascularized representation of the pancreas in real time. While no model will ever be as complex and nuanced as the original subject, we contend that ours represents a first in the field: a section of the human pancreas in vivo in a completely controlled and accessible environment that permits visualization of (and intervention in) the dynamic growth of pre-existing islets and the appearance of neogenic β-cells over weeks and months.
