Biology subjects

De Man, R.

Publications and source records attributed to De Man, R..

6 recordsLinked to original sources

bioRxiv2026

Alveolar niche disruption and aberrant epithelial reprogramming are early hallmarks of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which the earliest cellular events driving fibrosis remain poorly defined. Here, we analyzed lung samples from three independent and unique cohorts of patients with early disease and preserved lung function (Florence, NIH, Forli), applying an integrated multi-modal approach combining single-nucleus RNA sequencing, bulk transcriptomics, immunostaining, and spatial transcriptomics. Single nuclear RNA sequencing of samples obtained by diagnostic bronchoscopic cryobiopsy (Florence, n= 22) revealed that early IPF is characterized by a marked shift in alveolar epithelial composition, with loss of AT1 and AT2 cells and the emergence of aberrant basaloid cells and alveolar epithelial intermediate cells. These populations exhibited transcriptional programs associated with epithelial plasticity and profibrotic signaling and closely resembled those observed in end-stage IPF. Higher proportions of aberrant basaloid and alveolar epithelial intermediate cells were associated with subsequent disease progression, whereas AT2 cell abundance correlated with preserved lung function. Fibrotic CTHRC1+ fibroblasts are largely restricted to advanced disease, while endothelial remodeling and inflammatory fibroblast states are already evident in early IPF. Spatial transcriptomic analyses confirmed early disruption of the alveolar niche, with replacement of normal epithelial-capillary interactions by aberrant epithelial and venous endothelial cells (Forli, n= 24); the findings were replicated through single cell RNA sequencing of samples obtained by video assisted thoracoscopy two decades earlier (NIH n=9). Together, these findings identify that alveolar niche remodeling with loss of its normal components, and emergence of aberrant basaloid cells are features of early IPF, highlighting epithelial dysfunction as a key potential target for therapeutic interventions in early disease.

genomics↗

bioRxiv2025

Proximal Pulmonary Artery Stiffening as a Biomarker of Cardiopulmonary Aging

The geroscience hypothesis suggests that understanding underlying ageing mechanisms will enable us to delay aging and lessen age-related disability and diseases. While hallmarks of ageing list multiple contributing factors, role of mechanics has only been recently recognized and increasingly appreciated. Here, we use mouse models of ageing to investigate changes in mechanics of the proximal pulmonary artery, lung and right ventricle function in ageing. We found an age-related decline in the capacity to store energy and increased circumferential stiffness of the proximal pulmonary artery with age that associated with a reorientation of collagen towards the circumferential direction, decreased exercise ability, and decreased function of the lung and right ventricle. The observed compromised mechanics in proximal pulmonary artery is consistent across multiple mouse models of accelerated ageing. Further, transcriptional changes in proximal pulmonary artery indicate that aging is associated with senescence of perivascular macrophages, adventitial fibroblasts, and medial smooth muscle cells. Older pulmonary arteries increase expression of genes associated with ECM turnover (including genes in the TGF{beta} pathway) and increased intercellular signaling amongst perivascular macrophages, fibroblasts and smooth muscle cells. Our results provide promising biomarkers of ageing for diagnosis and potential pathways and molecular targets for targeting anti-ageing therapies.

physiology↗

bioRxiv2025

Hypoxia-Induced Cardiopulmonary Remodeling and Recovery: Critical Roles of the Proximal Pulmonary Artery, Macrophages, and Exercise

Hypoxemia impairs cardiopulmonary function. We investigated pulmonary artery remodeling in mice exposed to chronic hypoxia for up to five weeks and quantified associated changes in cardiac and lung function, without or with subsequent normoxic recovery in the absence or presence of exercise or pharmacological intervention. Hypoxia-induced stiffening of the proximal pulmonary artery stemmed primarily from remodeling of the adventitial collagen, which resulted in part from altered inter-cellular signaling associated with phenotypic changes in the mural smooth muscle cells and macrophages. Such stiffening appeared to precede and associate with both right ventricular and lung dysfunction, with changes emerging to similar degrees regardless of the age of onset of hypoxia during postnatal development. Key homeostatic target values of the wall mechanics were recovered by the pulmonary arteries with normoxic recovery while other values recovered only partially. Overall cardiopulmonary dysfunction due to hypoxia was similarly only partially reversible. Remodeling of the cardiopulmonary system due to hypoxia is a complex, multi-scale process that involves maladaptations of the proximal pulmonary artery.

physiology↗

bioRxiv2025

The Binary Cellular Biology of Human Growth I Quantifying the Creation and Growth of the Body and its Parts

Assessing and understanding the Growth and Development of animals generally, and of human fetuses specifically, provides essential information for the management of the health of the newborn and its mother. Here we show that a consideration of the formation of the body, in units of numbers of cells, N, and the change in these numbers by the binary either/or decisions of cells to divide or not, an approach we call Binary Cellular Analysis, provides new insights and new equations for quantifying the growth and development of the body and its parts. These equations include: 1) The Binary Cellular Universal Growth Equation, which captures growth from conception to adulthood, and provides a method for biologically-based, data-driven, Growth Curves; 2) The Binary Cellular Universal Mitotic Fraction Equation, which lies within the Binary Cellular Universal Growth Equation, and captures the mechanism of growth to adult size, control of cell division; 3) The Binary Cellular Allometric Growth Equation, which captures the creation and growth of the Tissues, Organs, and Anatomical Structures of the body, and how the embryo creates each Body Part from a Single Founder Cell; and, 4) Binary Cellular Estimated Fetal Weight Equations, derived from the Binary Cellular Allometric Growth Equation, which captures the relationship between Ultrasound Measurement and the Size of the body as a whole. These equations capture the developmental process of Cellular Selection, resulting from Differential Cellular Proliferation, which molds the formation of the body from a single fertilized ovum into a multicellular animal. The parameters of these equations both capture the differences in Size and Growth between animals across the taxonomic spectrum, and between human fetuses, as well as identify the individual mechanisms of mitosis that drive Growth and Development. From the Binary Cellular Universal Growth Equation, the Growth of human fetuses can be measured, thus providing a much-needed tool for understanding the biological forces that cause a fetus to grow to Small, Average, or Large Size at birth, for providing the basis of biologically-based, data-driven, Growth Curves, and for assisting the management of the obstetric care of the fetus and its mother.

developmental biology↗

bioRxiv2023

A Multi-omic Analysis of the Human Lung Reveals Distinct Cell Specific Aging and Senescence Molecular Programs

Age is a major risk factor for lung disease. To understand the mechanisms underlying this association, we characterized the changing cellular, genomic, transcriptional, and epigenetic landscape of lung aging using bulk and single-cell RNAseq (scRNAseq) data. Our analysis revealed age-associated gene networks that reflected hallmarks of aging, including mitochondrial dysfunction, inflammation, and cellular senescence. Cell type deconvolution revealed age-associated changes in the cellular composition of the lung: decreased alveolar epithelial cells and increased fibroblasts and endothelial cells. In the alveolar microenvironment, aging is characterized by decreased AT2B cells and reduced surfactant production, a finding that was validated by scRNAseq and IHC. We showed that a previously reported senescence signature, SenMayo, captures cells expressing canonical senescence markers. SenMayo signature also identified cell-type specific senescence-associated co-expression modules that have distinct molecular functions, including ECM regulation, cell signaling, and damage response pathways. Analysis of somatic mutations showed that burden was highest in lymphocytes and endothelial cells and was associated with high expression of senescence signature. Finally, aging and senescence gene expression modules were associated with differentially methylated regions, with inflammatory markers such as IL1B, IL6R, and TNF being significantly regulated with age. Our findings provide new insights into the mechanisms underlying lung aging and may have implications for the development of interventions to prevent or treat age-related lung diseases.

genomics↗

bioRxiv2021

How Our Cells Become Our Selves: The Cellular Phylodynamic Biology of Growth and Development

Our lives begin with 1 cell, then 2, then 4, then the trillion cell adult, comprised of cell lineages, tissues, organs. How does this occur? Examination in numbers of cells, N, Cellular Phylodynamics, revealed two previously unappreciated processes: UNI-GROWTH, the slowing of growth that occurs as we become larger, caused by fewer cells dividing, captured by the Universal Mitotic Fraction and Universal Growth Equations, with accuracy confirmed for 13 species, including nematodes, mollusks, and vertebrates; and ALLO-GROWTH, the creation of body parts from Founder Cells, captured by the Cellular Allometric Growth Equation, which describes mitotic expansion by Cell-Heritable change in the Cell Cycle Time. These equations can generate cell lineage approximations, bringing the power of coalescent theory to developmental biology.

developmental biology↗