Complementary and Inducible creERT2 Mouse Models for Functional Evaluation of Endothelial Cell Subtypes in the Bone Marrow DOI Creative Commons
Michael G. Poulos,

Pradeep Ramalingam,

Agatha Winiarski

et al.

Stem Cell Reviews and Reports, Journal Year: 2024, Volume and Issue: 20(4), P. 1135 - 1149

Published: March 4, 2024

Abstract In the adult bone marrow (BM), endothelial cells (ECs) are an integral component of hematopoietic stem cell (HSC)-supportive niche, which modulates HSC activity by producing secreted and membrane-bound paracrine signals. Within BM, distinct vascular arteriole, transitional, sinusoidal EC subtypes display unique expression profiles create anatomically-discrete microenvironments. However, relative contributions in supporting hematopoiesis is unclear. Moreover, constitutive off-target currently available endothelial-specific endothelial-subtype-specific murine cre lines potentially confound data analysis interpretation. To address this, we describe two tamoxifen-inducible -expressing lines, Vegfr3-creER T2 Cx40-creER , that efficiently label sinusoidal/transitional arteriole endothelium respectively marrow, without or perivascular cells. Utilizing established mouse model -dependent recombination constitutively-activates MAPK signaling within endothelium, identify ECs as driver MAPK-mediated dysfunction. These results define complementary creER functionally-discrete non-overlapping populations providing a robust toolset to investigate differential maintaining homeostasis. Graphical

Language: Английский

Emerging roles of nerve‐bone axis in modulating skeletal system DOI
Jingya Li, Zhuoyuan Zhang, Jinru Tang

et al.

Medicinal Research Reviews, Journal Year: 2024, Volume and Issue: 44(4), P. 1867 - 1903

Published: Feb. 29, 2024

Over the past decades, emerging evidence in literature has demonstrated that innervation of bone is a crucial modulator for skeletal physiology and pathophysiology. The nerve-bone axis sparked extensive preclinical clinical investigations aimed at elucidating contribution crosstalks to skeleton metabolism, homeostasis, injury repair through perspective neurobiology. To date, peripheral nerves have been widely reported mediate growth development fracture healing via secretion neurotransmitters, neuropeptides, axon guidance factors, neurotrophins. Relevant studies further identified several critical neural pathways stimulate profound alterations cell biology, revealing complex interplay between nerve systems. In addition, inspired by crosstalk, novel drug delivery systems bioactive materials developed emulate facilitate process natural neuromodulation, eventually boosting osteogenesis ideal tissue regeneration. Overall, this work aims review research findings contribute deepening current understanding axis, bringing forth some schemas can be translated into scenario highlight roles neuromodulation system.

Language: Английский

Citations

17
Clonal hematopoiesis and its impact on the aging osteo-hematopoietic niche DOI Creative Commons
Susann Winter, Katharina S. Götze, Judith S. Hecker

et al.

Leukemia, Journal Year: 2024, Volume and Issue: 38(5), P. 936 - 946

Published: March 21, 2024

Clonal hematopoiesis (CH) defines a premalignant state predominantly found in older persons that increases the risk of developing hematologic malignancies and age-related inflammatory diseases. However, for malignant transformation or non-malignant disorders is variable difficult to predict, defining clinical relevance specific candidate driver mutations individual carriers has proved be challenging. In addition cell-intrinsic mechanisms, mutant cells rely on alter cell-extrinsic factors from bone marrow (BM) niche, which complicates prediction cell's fate shifting pre-malignant microenvironment. Therefore, identifying insidious potentially broad impact supportive niches immune function CH aims understand subtle differences enable yield different outcomes. Here, we review changes aging BM niche emerging evidence supporting concept can progressively components local These alterations may have profound implications functionality osteo-hematopoietic overall health, consequently fostering conducive environment continued development progression CH. We also provide an overview latest technology developments study spatiotemporal dependencies ideally context longitudinal studies following over time. Finally, discuss aspects carrier management practice, based work our group others.

Language: Английский

Citations

13
Skeletal interoception in osteoarthritis DOI Creative Commons
Dinglong Yang,

Jiawen Xu,

Ke Xu

et al.

Bone Research, Journal Year: 2024, Volume and Issue: 12(1)

Published: April 1, 2024

Abstract The interoception maintains proper physiological conditions and metabolic homeostasis by releasing regulatory signals after perceving changes in the internal state of organism. Among its various forms, skeletal specifically regulates bones. Osteoarthritis (OA) is a complex joint disorder involving cartilage, subchondral bone, synovium. bone undergoes continuous remodeling to adapt dynamic loads. Recent findings highlight that mediated aberrant mechanical loads contributes pathological resulting sclerosis OA. also potential mechanism for chronic synovial inflammation In this review, we offer general overview interoception, microenviroment remedeling. We discuss role abnormal OA, as well prospects challenges exploring novel OA therapies target interoception.

Language: Английский

Citations

13
Bone marrow niches for hematopoietic stem cells: life span dynamics and adaptation to acute stress DOI
Johanna Hofmann, Konstantinos D. Kokkaliaris

Blood, Journal Year: 2024, Volume and Issue: 144(1), P. 21 - 34

Published: April 5, 2024

Language: Английский

Citations

10
Bone marrow niches for hematopoietic stem cells DOI Creative Commons
Ana L. Pereira, Serena Galli, César Nombela‐Arrieta

et al.

HemaSphere, Journal Year: 2024, Volume and Issue: 8(8)

Published: July 31, 2024

Abstract Hematopoietic stem cells (HSCs) are the cornerstone of hematopoietic system. HSCs sustain continuous generation mature blood derivatives while self‐renewing to preserve a relatively constant pool progenitors throughout life. Yet, long‐term maintenance functional exclusively takes place in association with their native tissue microenvironment bone marrow (BM). have been long proposed reside fixed and identifiable anatomical units found complex BM landscape, which control identity fate deterministic manner. In last decades, tremendous progress has made dissection cellular molecular fabric BM, structural organization governing function, plethora interactions established by HSCs. Nonetheless, holistic model mechanisms controlling HSC regulation niche is lacking date. Here, we provide an overview our current understanding anatomy, localization, crosstalk within local neighborhoods murine human tissues, highlight fundamental open questions on how functionally integrate microenvironment.

Language: Английский

Citations

10
Hallmarks of regeneration DOI
Kenneth D. Poss, Elly M. Tanaka

Cell stem cell, Journal Year: 2024, Volume and Issue: 31(9), P. 1244 - 1261

Published: Aug. 19, 2024

Language: Английский

Citations

10
Deep imaging of LepR+ stromal cells in optically cleared murine bone hemisections DOI Creative Commons
Yuehan Ni, Jun Wu, Fengqi Liu

et al.

Bone Research, Journal Year: 2025, Volume and Issue: 13(1)

Published: Jan. 12, 2025

Tissue clearing combined with high-resolution confocal imaging is a cutting-edge approach for dissecting the three-dimensional (3D) architecture of tissues and deciphering cellular spatial interactions under physiological pathological conditions. Deciphering interaction leptin receptor-expressing (LepR+) stromal cells other compartments in bone marrow crucial deeper understanding stem cell niche skeletal tissue. In this study, we introduce an optimized protocol 3D analysis tissues, enabling visualization hematopoietic cells, especially LepR+ within optically cleared hemisections. Our method preserves tissue extendable to sites such as calvaria vertebrae. The entails fixation, decalcification, cryosectioning reveal cavity. Completed approximately 12 days, process yields highly transparent that maintain genetically encoded or antibody-stained fluorescent signals. hemisections are compatible diverse antibody labeling strategies. Confocal microscopy these samples allows qualitative quantitative image using Aivia Bitplane Imaris software, assessing spectrum parameters. With proper storage, signal stained remains intact at least 2-3 months. This robust, straightforward implement, reproducible, offering valuable tool studies.

Language: Английский

Citations

1
Periarteriolar niches become inflamed in aging bone marrow, remodeling the stromal microenvironment and depleting lymphoid progenitors DOI Creative Commons
Liming Du,

Maria Angelica Freitas-Cortez,

Jingzhu Zhang

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(11)

Published: March 10, 2025

In early postnatal and young adult bone marrow, Leptin receptor–expressing (LepR + ) stromal cells endothelial synthesize factors required for hematopoietic stem cell (HSC) maintenance, including Stem Cell Factor (SCF) Cxcl12. However, little is known about how these change during aging. We performed single-cell RNA sequencing of mouse marrow at 2, 12, 24 mo age. identified five transcriptionally distinct subsets LepR cells, all which expressed the highest levels Scf Cxcl12 in throughout life. aging SCF from but not continued to be necessary maintenance HSCs restricted progenitors. arteriolar other periarteriolar increasing interferon This increased numbers Sca1 Cxcl9 with an inflammatory gene signature depleted lymphoid progenitors, least some are also periarteriolar. The environment thus became particularly inflamed aging, remodeling microenvironment depleting progenitors interferon-dependent manner.

Language: Английский

Citations

1
Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow DOI Creative Commons
Tongling Huang,

Zhaocheng Lu,

Zihui Wang

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 4, 2024

Abstract Excessive bone marrow adipocytes (BMAds) accumulation often occurs under diverse pathophysiological conditions associated with deterioration. Estrogen-related receptor α (ESRRA) is a key regulator responding to metabolic stress. Here, we show that adipocyte-specific ESRRA deficiency preserves osteogenesis and vascular formation in adipocyte-rich upon estrogen or obesity. Mechanistically, adipocyte interferes E2/ESR1 signaling resulting transcriptional repression of secreted phosphoprotein 1 ( Spp1 ); yet positively modulates leptin expression by binding its promoter. abrogation results enhanced SPP1 decreased secretion from both visceral BMAds, concertedly dictating stromal stem cell fate commitment restoring type H vessel formation, constituting feed-forward loop for formation. Pharmacological inhibition protects obese mice against loss high adiposity. Thus, our findings highlight therapeutic approach via targeting preserve especially detrimental milieu.

Language: Английский

Citations

8
The role of the haematopoietic stem cell niche in development and ageing DOI
Terri L Cain, Marta Derecka, Shannon McKinney‐Freeman

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 10, 2024

Language: Английский

Citations

7