Biology subjects

Russell, J. P.

Publications and source records attributed to Russell, J. P..

4 recordsLinked to original sources

bioRxiv2023

SOX2+ sustentacular cells are stem cells of the postnatal adrenal medulla

Renewal of the catecholamine-secreting chromaffin cell population of the adrenal medulla is necessary for physiological homeostasis throughout life. Definitive evidence for the presence or absence of an adrenomedullary stem cell has been enigmatic. In this work, we demonstrate that a subset of sustentacular cells endowed with a support role, are in fact adrenomedullary stem cells. Through genetic tracing and comprehensive transcriptomic data of the mouse adrenal medulla, we show that cells expressing Sox2/SOX2 specialise as a unique postnatal population from embryonic Schwann Cell Precursors and are also present in the normal adult human adrenal medulla. Postnatal SOX2+ cells give rise to chromaffin cells of both the adrenaline and noradrenaline lineages in vivo and in vitro. We reveal that SOX2+ stem cells have a second, paracrine role in maintaining adrenal chromaffin cell homeostasis, where they promote proliferation through paracrine secretion of WNT6. This work identifies SOX2+ cells as a true stem cell for catecholamine-secreting chromaffin cells.

developmental biology↗

bioRxiv2021

Peptidylarginine deiminase IV (PADI4) is not essential for cell-autonomous HSC maintenance and normal haematopoiesis

Peptidylarginine deiminases (PADIs, or PADs) are emerging as key regulators of human physiology and pathophysiology. The nuclear deiminase PADI4 regulates embryonic stem cell pluripotency, however its role in adult stem cells is unknown. PADI4 is expressed most highly in the bone marrow (BM), where it is found as part of a self-renewal-associated gene signature and shown to modulate the function of critical transcriptional regulators such as Tal1 and c-Myc, suggesting that it regulates haematopoietic development or regeneration. We investigated the functional significance of PADI4 in haematopoietic stem cell (HSC) biology and normal haematopoiesis. We employed two conditional mouse models of tissue-specific Padi4 ablation, where Padi4 was completely deleted either after the emergence of HSCs, or acutely in the BM of adult mice. We found that loss of PADI4 does not significantly affect HSC self-renewal or differentiation potential upon injury or serial transplantation, nor does it lead to exhaustion or premature ageing of HSCs. Thus, surprisingly, PADI4 is dispensable for cell-autonomous HSC maintenance, differentiation and haematopoietic regeneration. This work has important implications for the clinical use of PADI4 inhibitors as therapeutic agents in autoimmunity and cancer. Key PointsO_LIPADI4 is dispensable for steady-state and post-transplantation haematopoiesis C_LIO_LIHSCs do not require intrinsic PADI4 activity to respond to haematopoietic injury C_LIO_LIPADI4 deficiency does not lead to premature HSC ageing or exhaustion C_LI

developmental biology↗

bioRxiv2020

Pituitary stem cells produce paracrine WNT signals to control the expansion of their descendant progenitor cells

In response to physiological demand, the pituitary gland generates new hormone-secreting cells from committed progenitor cells throughout life. It remains unclear to what extent pituitary stem cells (PSCs), which uniquely express SOX2, contribute to pituitary growth and renewal. Moreover, neither the signals that drive proliferation nor their sources have been elucidated. We have used genetic approaches in the mouse, showing that the WNT pathway is essential for proliferation of all lineages in the gland. We reveal that SOX2+ stem cells are a key source of WNT ligands. By blocking secretion of WNTs from SOX2+ PSCs in vivo, we demonstrate that proliferation of neighbouring committed progenitor cells declines, demonstrating that progenitor multiplication depends on the paracrine WNT secretion from SOX2+ PSCs. Our results indicate that stem cells can hold additional roles in tissue expansion and homeostasis, acting as paracrine signalling centres to coordinate the proliferation of neighbouring cells.

developmental biology↗

bioRxiv2018

Homeostatic and tumourigenic activity of SOX2+ pituitary stem cells is controlled by the LATS/YAP/TAZ cascade

SOX2 positive pituitary stem cells (PSCs) are specified embryonically and persist throughout life, giving rise to all pituitary endocrine lineages. We have previously shown the activation of the MST/LATS/YAP/TAZ signalling cascade in the developing and postnatal mammalian pituitary. Here, we investigate the function of this pathway during pituitary development and in the regulation of the SOX2 cell compartment. Through loss- and gain-of-function genetic approaches, we reveal that restricting YAP/TAZ activation during development is essential for normal organ size and specification from SOX2+ PSCs. Postnatal deletion of LATS kinases and subsequent upregulation of YAP/TAZ leads to uncontrolled clonal expansion of the SOX2+ PSCs and disruption of their differentiation, causing the formation of non-secreting, aggressive pituitary tumours. In contrast, sustained expression of YAP alone results in expansion of SOX2+ PSCs capable of differentiation and devoid of tumourigenic potential. Our findings identify the LATS/YAP/TAZ signalling cascade as an essential component of PSC regulation in normal pituitary physiology and tumourigenesis.

developmental biology↗