Deciphering the Complexities of Adult Human Steady State and Stress-Induced Hematopoiesis: Progress and Challenges

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(2), С. 671 - 671

Опубликована: Янв. 14, 2025

Human hematopoietic stem cells (HSCs) have traditionally been viewed as self-renewing, multipotent with enormous potential in sustaining essential steady state blood and immune cell production throughout life. Indeed, around 86% (1011-1012) of new generated daily a healthy young human adult are origin. Therapeutically, HSCs contributed to over 1.5 million transplants (HCTs) globally, making this the most successful regenerative therapy date. We will commence review by briefly highlighting selected key achievements (from 1868 end 20th century) that accomplishment. Much our knowledge hematopoiesis is based on small animal models that, despite their importance, do not always recapitulate hematopoiesis. Given this, we critically progress challenges faced identifying tracing lineage differentiation trajectories, referring murine studies needed. Moving forward given dynamic can readily adjust variety stressors, then discuss recent research advances contributing understanding (i) which HSPCs maintain hematopoiesis, (ii) where these located, (iii) mechanisms come into play when homeostatic switches stress-induced or emergency

Язык: Английский

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Bone Marrow Niche in Cardiometabolic Disease: Mechanisms and Therapeutic Potential

Circulation Research, Год журнала: 2025, Номер 136(3), С. 325 - 353

Опубликована: Янв. 30, 2025

Cardiovascular and cardiometabolic diseases are leading causes of morbidity mortality worldwide, driven in part by chronic inflammation. Emerging research suggests that the bone marrow microenvironment, or niche, plays a critical role both immune system regulation disease progression. The niche is essential for maintaining hematopoietic stem cells (HSCs) orchestrating hematopoiesis. Under normal conditions, this ensures return to homeostasis after acute stress. However, setting inflammatory conditions such as those seen diseases, it becomes dysregulated, enhanced myelopoiesis activation. This review explores reciprocal relationship between highlighting how alterations contribute development regulates HSCs through complex interactions with stromal cells, endothelial signaling molecules. hypertension, atherosclerosis, diabetes, signals disrupt balance HSC self-renewal differentiation, promoting excessive production proinflammatory myeloid exacerbate disease. Key mechanisms discussed include effects hyperlipidemia, hyperglycemia, sympathetic nervous activation on proliferation differentiation. Furthermore, emphasizes epigenetic modifications metabolic reprogramming creating trained immunity, phenomenon whereby acquire long-term characteristics sustain states. Finally, we explore therapeutic strategies aimed at targeting mitigate inflammation its sequelae. Novel interventions modulate hematopoiesis restore hold promise treatment diseases. By interrupting vicious cycle dysregulation, therapies may offer new avenues reducing cardiovascular risk improving patient outcomes.

Язык: Английский

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KLF4 enhances transplantation-induced hematopoiesis by inhibiting TLRs and non-canonical NFκB signaling at a steady state.

Experimental Hematology, Год журнала: 2025, Номер unknown, С. 104730 - 104730

Опубликована: Фев. 1, 2025

Язык: Английский

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Leukemogenic Kras mutation reprograms multipotent progenitors to facilitate its spread through the hematopoietic system

The Journal of Experimental Medicine, Год журнала: 2025, Номер 222(6)

Опубликована: Март 12, 2025

Leukemia-driving mutations are thought to arise in hematopoietic stem cells (HSC), yet the natural history of their spread is poorly understood. We genetically induced within endogenous murine HSC and traced them unmanipulated animals. In contrast associated with clonal hematopoiesis (such as Tet2 deletion), leukemogenic KrasG12D mutation dramatically accelerated contribution all lineages. The acceleration was mediated by KrasG12D-expressing multipotent progenitors (MPP) that lacked self-renewal but showed increased proliferation aberrant transcriptome. deletion osteopontin, a secreted negative regulator stem/progenitor cells, delayed early expansion mutant progenitors. KrasG12D-carrying CXCR4-driven motility bone marrow, blockade CXCR4 reduced MPP vivo. Finally, therapeutic KRASG12D spared mature progeny. Thus, transforming facilitate own from reprogramming MPP, creating preleukemic state via two-component circuit.

Язык: Английский

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Ontogeny Dictates Oncogenic Potential, Lineage Hierarchy, and Therapy Response in Pediatric Leukemia

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 20, 2025

Accumulating evidence links pediatric cancers to prenatal transformation events, yet the influence of developmental stage on oncogenesis remains elusive. We investigated how hematopoietic stem cell stages affect leukemic transformation, disease progression, and therapy response using a novel, humanized model NUP98::NSD1-driven acute myeloid leukemia, that is particularly aggressive with WT1 co-mutations. Fetal-derived cells readily transform into mutations further enhance stemness alter lineage hierarchy. In contrast, from later become progressively resistant transformation. Single-cell analyses revealed fetal-origin leukemia exhibit greater quiescence reliance oxidative phosphorylation than their postnatal counterparts. These differences drive distinct therapeutic responses, despite identical oncogenic mutations. patients, onco-fetal transcriptional programs correlate worse outcomes. By targeting key vulnerabilities cells, we identified combination therapies significantly reduce aggressiveness, highlighting critical role ontogeny in cancer treatment.

Язык: Английский

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Two distinct fetal‐type signatures characterize juvenile myelomonocytic leukemia

HemaSphere, Год журнала: 2025, Номер 9(3)

Опубликована: Март 1, 2025

Abstract Juvenile myelomonocytic leukemia (JMML) is an aggressive clonal myeloproliferative neoplasm that affects infants and young children. The narrow window of onset suggests age‐related factors are involved in leukemogenesis. To investigate whether ontogeny‐related features JMML oncogenesis, we compared the gene expression profile hematopoietic progenitor cells isolated from patients with healthy individuals at different stages ontogeny. This analysis identified two main groups patients. In first group, progenitors exhibited a similar to embryo‐fetal progenitors. Progenitors showed strong monocytic identity as evidenced by overexpression monocytic/dendritic, inflammasome, innate immune markers. resembled monocyte‐predominant myelopoiesis characteristic normal fetal hematopoiesis. However, second despite evidence developmental dysregulation indicated aberrant signature master oncofetal regulator LIN28B, clustered separately prenatal postnatal fractions. These findings highlight intricate relationship between development, which will help inform future therapeutic approaches for this rare but severe form leukemia.

Язык: Английский

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Direct megakaryopoiesis

Current Opinion in Hematology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 8, 2025

Purpose of review Megakaryocytes are large, polyploid cells that produce platelets and originate from hematopoietic stem (HSCs) in the bone marrow. While classical paradigm, megakaryocytes generated a stepwise fashion through increasingly committed progenitor stages, studies using in-vivo barcoding, transplantation, in-vitro culture have suggested that, addition, more direct pathway existed. The relevance this its functional phenotypic characteristics were unclear, however. Recent findings publications fate-mapping single-cell transplantation now unequivocally demonstrate existence megakaryocyte differentiation pathway, provide molecular characterization, indicate distinct roles regulation both pathways. originates separate subset ‘top’ HSCs, is enhanced by stress, inflammation aging, bypasses multipotential progenitors, may be active myeloproliferative neoplasms, generates phenotypically progenitors reactive platelets. Summary Novel insights into deeper understanding HSC biology, hematological recovery after myeloablation, aging system, suggest contribute to increase thrombotic incidents with age neoplasms.

Язык: Английский

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Hematopoietic stem cell state and fate in trained immunity

Cell Communication and Signaling, Год журнала: 2025, Номер 23(1)

Опубликована: Апрель 14, 2025

Язык: Английский

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Tetrahydroxy stilbene glucoside rejuvenates aging hematopoietic stem cells with predilection for lymphoid differentiation via AMPK and Tet2

Journal of Advanced Research, Год журнала: 2024, Номер unknown

Опубликована: Май 1, 2024

Aging of hematopoietic stem cells (HSCs) has emerged as an important challenge to human health. Recent advances have raised the prospect rejuvenating aging HSCs via specific medical interventions, including pharmacological treatments. Nonetheless, efforts develop such drugs are still in infancy until now. We aimed screen prospective agents that can rejuvenate and explore potential mechanisms. screened a set natural anti-aging compounds through oral administration sub-lethally irradiated mice, identified 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) potent agent for HSCs. Then naturally aged mice were used follow-up assessment determine HSC TSG. Finally, based on transcriptome DNA methylation analysis, we validated role AMP-activated protein kinase (AMPK)-ten-eleven-translocation 2 (Tet2) axis (the AMPK-Tet2 axis) underlying mechanisms TSG ameliorating aging. treatment not only significantly increased absolute number common lymphoid progenitors (CLPs) along with B lymphocytes, but also boosted HSCs/CLPs repopulation mice. Further elaborated mechanism research demonstrated supplementation restored stemness HSCs, well promoted epigenetic reprograming was associated improved regenerative capacity rate lymphopoiesis. Such effects diminished when co-treated AMPK inhibitor, or it performed Tet2 knockout senescent assay. is effective by modulating AMPK- thus represents candidate developing therapies.

Язык: Английский

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From Marrow to Bone and Fat: Exploring the Multifaceted Roles of Leptin Receptor Positive Bone Marrow Mesenchymal Stromal Cells

Cells, Год журнала: 2024, Номер 13(11), С. 910 - 910

Опубликована: Май 24, 2024

The bone marrow (BM) stromal cell microenvironment contains non-hematopoietic cells called mesenchymal (MSCs). MSCs are plastic adherent, form CFU-Fs, and give rise to osteogenic, adipogenic, chondrogenic progenitors, most importantly provide HSC niche factor chemokine C-X-C motif ligand 12 (CXCL12) stem (SCF). Different authors have defined different markers for mouse MSC identification like PDGFR+Sca-1+ subsets, Nestin+, or LepR+ cells. Of these, the major source of SCF CXCL12 in BM play a role maintenance hematopoiesis. bones adipocytes, further regulating microenvironment. In adult BM, quiescent but after fracture irradiation, they proliferate differentiate into lineage adipogenic and/or They also crucial steady-state hematopoiesis process, as well hematopoietic regeneration homing (HSCs) myeloablative injury transplantation. line sinusoidal cavities, maintain trabeculae formation, space retention. However, subset is heterogeneous; some subsets higher potential, while others express osteollineage-biased genes. transcription factors Early B 3 (EBF3) RunX2 help this balance between self-renewing committed states, whether osteogenic adipogenic. study holds immense promise advancing our understanding biology, tissue regeneration, metabolic disorders, immune responses. review, we will discuss origin resident cells, subtypes, maintaining hematopoiesis, osteogenesis, adipogenesis following their multifaceted impact.

Язык: Английский

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