Scholarlink

<p>Idiopathic dyskeratosis congenita (DC) is a disorder characterized by mucocutaneous alterations, bone-marrow failure, immune deficiency, liver cirrhosis, and other morbidities, due to alterations in telomere maintenance, which, in most cases, lead to short telomeres and poor tissue regeneration and function. The main cause of mortality is bone-marrow failure. A non-local diffusion–advection model with zero-flux boundary conditions is used to simulate the generational and temporal evolution of a hematopoietic stem cell (HSC) population in order to investigate the progression of DC. Blood-cell production from progenitor cells that had exited the HSC compartment was quantified. The influence of variations in initial proliferation potential (<InlineEquation ID="IEq1"><EquationSource Format="TEX">\(x_H\)</EquationSource></InlineEquation>) and telomerase activity (<i>s</i>) on the onset of pancytopenia was examined. Age-and weight-dependent blood cell demands are modeled for both sexes, establishing a physiological baseline against which DC-related deficiencies are compared. Simulations revealed that lower <InlineEquation ID="IEq2"><EquationSource Format="TEX">\(x_H\)</EquationSource></InlineEquation> values and reduced telomerase activity accelerate stem cell exhaustion, resulting in early pancytopenia, sometimes before age of 2 years. In contrast, patients with moderately higher <InlineEquation ID="IEq3"><EquationSource Format="TEX">\(x_H\)</EquationSource></InlineEquation> values developed pancytopenia later in life, with onset delayed until the third or fourth decade. Treatment simulations demonstrated that a two-year course of danazol, a synthetic androgen, can slow telomere attrition. These findings suggest that pharmacological intervention may delay hematopoietic failure and possibly improve the production of oocytes with better-preserved telomeres in female DC patients. Our model provides a valuable framework for assessing (or understanding, or both) disease progression and evaluating therapeutic strategies in telomeropathy-associated bone marrow failure.</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

Mathematical modelling of premature haematopoietic ageing in dyskeratosis congenita

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月24日

查看全文
  • Ana M. Portillo,
  • Juan A. García-Velasco,
  • Elisa Varela

摘要

Idiopathic dyskeratosis congenita (DC) is a disorder characterized by mucocutaneous alterations, bone-marrow failure, immune deficiency, liver cirrhosis, and other morbidities, due to alterations in telomere maintenance, which, in most cases, lead to short telomeres and poor tissue regeneration and function. The main cause of mortality is bone-marrow failure. A non-local diffusion–advection model with zero-flux boundary conditions is used to simulate the generational and temporal evolution of a hematopoietic stem cell (HSC) population in order to investigate the progression of DC. Blood-cell production from progenitor cells that had exited the HSC compartment was quantified. The influence of variations in initial proliferation potential (\(x_H\)) and telomerase activity (s) on the onset of pancytopenia was examined. Age-and weight-dependent blood cell demands are modeled for both sexes, establishing a physiological baseline against which DC-related deficiencies are compared. Simulations revealed that lower \(x_H\) values and reduced telomerase activity accelerate stem cell exhaustion, resulting in early pancytopenia, sometimes before age of 2 years. In contrast, patients with moderately higher \(x_H\) values developed pancytopenia later in life, with onset delayed until the third or fourth decade. Treatment simulations demonstrated that a two-year course of danazol, a synthetic androgen, can slow telomere attrition. These findings suggest that pharmacological intervention may delay hematopoietic failure and possibly improve the production of oocytes with better-preserved telomeres in female DC patients. Our model provides a valuable framework for assessing (or understanding, or both) disease progression and evaluating therapeutic strategies in telomeropathy-associated bone marrow failure.