Biology subjects

Heber-Katz, E.

Publications and source records attributed to Heber-Katz, E..

3 recordsLinked to original sources

bioRxiv2023

Epithelial-Mesenchymal Transition: An Organizing Principle of Mammalian Regeneration

The MRL mouse strain is one of the few examples of a mammal capable of healing appendage wounds by regeneration, a process that begins with the formation of a blastema, a structure containing de-differentiating mesenchymal cells. HIF-1 expression in the nascent MRL wound site blastema is one of the earliest identified events and is sufficient to initiate the complete regenerative program. However, HIF-1 regulates many cellular processes modulating the expression of hundreds of genes. A later signal event is the absence of a functional G1 checkpoint leading to G2 cell cycle arrest with increased cellular DNA but little cell division seen in the blastema. This lack of mitosis in MRL blastema cells is also a hallmark of regeneration in classical invertebrate and vertebrate regenerators such as the planaria, hydra, and newt. Here, we explore the cellular events occurring between HIF-1 upregulation and its regulation of the genes involved in G2 arrest (EVI-5, {gamma}H3, Wnt5a, and ROR2), and identify EMT (Twist, Slug) and chromatin remodeling (EZH-2 and H3K27me3) as key intermediary processes. The locus of these cellular events is highly regionalized within the blastema, occurring in the same cells as determined by double staining using immunohistochemistry and FACS analysis, and appear as EMT and chromatin remodeling followed by G2 arrest determined by kinetic expression studies.

developmental biology↗

bioRxiv2022

Neovascularization and the recruitment of CD31+ cells from the bone marrow are unique under regenerative but not wound repair conditions

The long-noted observation that endostatin is a potent inhibitor of tumor vasculature but has little or no effect on wound repair or pregnancy remains an "as of yet unexplained but remarkable phenomenon"(1). However, there is another path to wound healing, epimorphic regeneration, and here we present data in mice demonstrating that endostatin is, in fact, a potent inhibitor of epimorphic regeneration. In this study, we show that a rege nerative response seen in the spontaneously regenerating MRL mouse involves CD31+ endothelial precursors that migrate from the bone marrow into the wound site and form new vessels, unlike that seen in the non-regenerating C57BL/6 mouse injury site. Furthermore, this appears to relate to the induction of HIF-1a, an inducer of regeneration (2). Inducing epimorphic regeneration in otherwise non-regenerating mice via an enhanced HIF-1a response by employing the PHD inhibitor 1,4-DPCA/hydrogel, a HIF-1a stabilizer, results in the same increased bone marrow-derived CD31+ endothelial precursor response and increased vasculogenesis. This regenerative response is completely blocked by endostatin, supporting the notion that vascularization induced during regeneration shares similarities to the tumor vasculature.

developmental biology↗

bioRxiv2021

Prolyl-hydroxylase inhibitor-induced regeneration of alveolar bone and soft tissue in a mouse model of ligature-induced periodontitis

Bone injuries and fractures reliably heal through a process of regeneration with restoration to original structure and function when the gap between adjacent sides of a fracture site is small. However, when there is significant volumetric loss of bone, bone regeneration usually does not occur. In the present studies, we explore a particular case of volumetric bone loss in a mouse model of human periodontal disease (PD) in which alveolar bone surrounding teeth is permanently lost and not replaced. This model employs the placement a ligature around the upper second molar which leads to inflammation and bone breakdown and faithfully replicates the bacterially-induced inflammatory etiology of human PD to induce bone degeneration. After 10 days, the ligature is removed and the mice are treated with a timed-release formulation of a small molecule inhibitor of prolylhydroxylases (PHDi; 1,4-DPCA) previously shown to induce epimorphic regeneration of soft tissue in non-regenerating mice. This PHDi induces high expression of HIF-1 and the regenerative response is completely blocked by siHIF1a. Here, we observe that timed-release 1,4-DPCA rapidly and completely restores bone and soft tissue with normal anatomic fidelity and with increased stem cell markers due to stem cell migration into the site and/or de-differentiation of local tissue, PDL cell proliferation, and increased vascularization. In-vitro studies using gingival tissue show that 1,4-DPCA indeed induces de-differentiation and the expression of stem cell markers but does not exclude the role of migrating stem cells.

developmental biology↗