Scholarlink

Background <p>Glucocorticoids (GCs) are key regulators of hematopoiesis, but the effects of chronically elevated endogenous GC levels on hematopoietic stem cell (HSC) function and immune cell development remain poorly understood.</p> Methods <p>We used a mouse model with adrenocortical cell-specific deletion of hypoxia-inducible factor-1 alpha (HIF1α; P2H1<sup>Ad.Cortex</sup>), which results in sustained and systemic elevation of GC. Hematopoietic stem and progenitor cell (HSPC) populations were analyzed phenotypically and functionally. Transplantation assays assessed the regenerative capacity of HSCs. To determine the role of glucocorticoid receptor (GR) signaling, bone marrow from GR-deficient or wild-type donors was transplanted into P2H1<sup>Ad.Cortex</sup> or wild-type (WT) recipients.</p> Results <p>Chronic GC exposure in P2H1<sup>Ad.Cortex</sup> mice resulted in HSPC expansion and promoted HSC quiescence and metabolic restraint. Functionally, these HSCs showed enhanced regenerative capacity with superior donor chimerism upon transplantation. There was a marked increase in myeloid progenitors and their progeny, including monocytes and granulocytes. In contrast, B-cell development was significantly impaired, with a developmental block at the pre-pro-B-cell stage. Transplantation studies confirmed that these effects were dependent on GR signaling.</p> Conclusions <p>Our study reveals a critical role for chronic GC–GR signaling in modulating HSC function, promoting myeloid output, and impairing B-cell development. The P2H1<sup>Ad.Cortex</sup> mouse model provides a valuable system to study the hematopoietic consequences of prolonged endogenous glucocorticoid exposure and may aid in understanding the hematologic complications of chronic GC therapy.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Hypoxia inducible factor 1α-driven steroidogenesis impacts systemic hematopoiesis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月25日

查看全文
  • Deepika Watts,
  • Nicolas Eberz,
  • Mangesh T. Jaykar,
  • Anupam Sinha,
  • Cagdas Ermis,
  • Johanna Tiebel,
  • Ulrike Baschant,
  • Martina Rauner,
  • Tatyana Grinenko,
  • Triantafyllos Chavakis,
  • Peter Mirtschink,
  • Ali El-Armouche,
  • Ben Wielockx

摘要

Background

Glucocorticoids (GCs) are key regulators of hematopoiesis, but the effects of chronically elevated endogenous GC levels on hematopoietic stem cell (HSC) function and immune cell development remain poorly understood.

Methods

We used a mouse model with adrenocortical cell-specific deletion of hypoxia-inducible factor-1 alpha (HIF1α; P2H1Ad.Cortex), which results in sustained and systemic elevation of GC. Hematopoietic stem and progenitor cell (HSPC) populations were analyzed phenotypically and functionally. Transplantation assays assessed the regenerative capacity of HSCs. To determine the role of glucocorticoid receptor (GR) signaling, bone marrow from GR-deficient or wild-type donors was transplanted into P2H1Ad.Cortex or wild-type (WT) recipients.

Results

Chronic GC exposure in P2H1Ad.Cortex mice resulted in HSPC expansion and promoted HSC quiescence and metabolic restraint. Functionally, these HSCs showed enhanced regenerative capacity with superior donor chimerism upon transplantation. There was a marked increase in myeloid progenitors and their progeny, including monocytes and granulocytes. In contrast, B-cell development was significantly impaired, with a developmental block at the pre-pro-B-cell stage. Transplantation studies confirmed that these effects were dependent on GR signaling.

Conclusions

Our study reveals a critical role for chronic GC–GR signaling in modulating HSC function, promoting myeloid output, and impairing B-cell development. The P2H1Ad.Cortex mouse model provides a valuable system to study the hematopoietic consequences of prolonged endogenous glucocorticoid exposure and may aid in understanding the hematologic complications of chronic GC therapy.