Adiponectin receptors sustain haematopoietic stem cells throughout adulthood by protecting them from inflammation

Meacham, Corbin E.; Jeffery, Elise; Burgess, Rebecca J.; Sivakumar, Charukesi D; Arora, Madison A; Stanley, Anne Marie; Colby, Emily M; Crane, Genevieve M.; Zhao, Zhiyu; Morrison, Sean J.

doi:10.1038/s41556-022-00909-9

Cited by 21 publications

(11 citation statements)

References 59 publications

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“…In addition, the tri-lineage differentiation capacity of MSCs impacts hematopoiesis in several ways. Lineage bias of HSCs and hematopoietic recovery are regulated differentially by factors released by osteo-primed or adipo-primed MSC populations 14,42,43 . Under 0.5 Gy irradiation, our results revealed preserved tri-lineage differentiation capacity of MSCs.…”

Section: Discussionmentioning

confidence: 99%

Ultralow-dose irradiation enables engraftment and intravital tracking of disease initiating niches in clonal hematopoiesis

Dissanayake,

Lee,

MacLiesh

et al. 2024

Preprint

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Recent advances in imaging suggested that spatial organization of hematopoietic cells in their bone marrow microenvironment (niche) regulates cell expansion, governing progression, and leukemic transformation of hematological clonal disorders. However, our ability to interrogate the niche in pre-malignant conditions has been limited, as standard murine models of these diseases rely largely on transplantation of the mutant clones into conditioned mice where the marrow microenvironment is compromised. Here, we leveraged live-animal microscopy and ultralow dose whole body or focal irradiation to capture single cells and early expansion of benign/pre-malignant clones in the functionally preserved microenvironment. 0.5 Gy whole body irradiation allowed steady engraftment of cells beyond 30 weeks compared to non-conditioned controls. In-vivo tracking and functional analyses of the microenvironment showed no change in vessel integrity, cell viability, and HSC-supportive functions of the stromal cells, suggesting minimal inflammation after the radiation insult. The approach enabled in vivo imaging of Tet2+/- and its healthy counterpart, showing preferential localization within a shared microenvironment while forming discrete micro-niches. Notably, stationary association with the niche only occurred in a subset of cells and would not be identified without live imaging. This strategy may be broadly applied to study clonal disorders in a spatial context.

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Section: Discussionmentioning

confidence: 99%

Ultralow-dose irradiation enables engraftment and intravital tracking of disease initiating niches in clonal hematopoiesis

Dissanayake,

Lee,

MacLiesh

et al. 2024

Preprint

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“…92 Interestingly, Meacham et al demonstrated a role for adiponectin in maintaining HSC self-renewal throughout aging and protecting HSCs from insults caused by inflammatory cytokines. 134 Notably, these effects were specific to HSCs and less prominent in differentiated cells.…”

Section: Skeletal Aging and The Bone Marrow Microenvironmentmentioning

confidence: 99%

The roles of bone remodeling in normal hematopoiesis and age-related hematological malignancies

et al. 2023

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Prior research establishing that bone interacts in coordination with the bone marrow microenvironment (BMME) to regulate hematopoietic homeostasis was largely based on analyses of individual bone-associated cell populations. Recent advances in intravital imaging has suggested that the expansion of hematopoietic stem cells (HSCs) and acute myeloid leukemia cells is restricted to bone marrow microdomains during a distinct stage of bone remodeling. These findings indicate that dynamic bone remodeling likely imposes additional heterogeneity within the BMME to yield differential clonal responses. A holistic understanding of the role of bone remodeling in regulating the stem cell niche and how these interactions are altered in age-related hematological malignancies will be critical to the development of novel interventions. To advance this understanding, herein, we provide a synopsis of the cellular and molecular constituents that participate in bone turnover and their known connections to the hematopoietic compartment. Specifically, we elaborate on the coupling between bone remodeling and the BMME in homeostasis and age-related hematological malignancies and after treatment with bone-targeting approaches. We then discuss unresolved questions and ambiguities that remain in the field.

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“…The adipocytes that arise from LepR + cells in adult bone marrow promote the regeneration of HSCs and haematopoiesis after myeloablation by synthesizing SCF 35 . LepR + cells and adipocytes also promote HSC maintenance and quiescence by secreting adiponectin, which suppresses inflammation 37 . In this article, bone marrow nerve fibers were found to be maintained by NGF synthesized by LepR + cells and, in turn, nerves promote haematopoietic and vascular regeneration by secreting adrenergic neurotransmitters that activate β2/β3 adrenergic receptor signaling in LepR + cells.…”

Section: Mainmentioning

confidence: 99%

Leptin receptor+ cells promote bone marrow innervation and regeneration by synthesizing nerve growth factor

Gao,

Murphy,

Peyer

et al. 2023

Nat Cell Biol

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The bone marrow contains peripheral nerves that promote haematopoietic regeneration after irradiation or chemotherapy (myeloablation), but little is known about how this is regulated. Here we found that nerve growth factor (NGF) produced by leptin receptor-expressing (LepR+) stromal cells is required to maintain nerve fibres in adult bone marrow. In nerveless bone marrow, steady-state haematopoiesis was normal but haematopoietic and vascular regeneration were impaired after myeloablation. LepR+ cells, and the adipocytes they gave rise to, increased NGF production after myeloablation, promoting nerve sprouting in the bone marrow and haematopoietic and vascular regeneration. Nerves promoted regeneration by activating β2 and β3 adrenergic receptor signalling in LepR+ cells, and potentially in adipocytes, increasing their production of multiple haematopoietic and vascular regeneration growth factors. Peripheral nerves and LepR+ cells thus promote bone marrow regeneration through a reciprocal relationship in which LepR+ cells sustain nerves by synthesizing NGF and nerves increase regeneration by promoting the production of growth factors by LepR+ cells.

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Adiponectin receptors sustain haematopoietic stem cells throughout adulthood by protecting them from inflammation

Cited by 21 publications

References 59 publications

Ultralow-dose irradiation enables engraftment and intravital tracking of disease initiating niches in clonal hematopoiesis

Ultralow-dose irradiation enables engraftment and intravital tracking of disease initiating niches in clonal hematopoiesis

The roles of bone remodeling in normal hematopoiesis and age-related hematological malignancies

Leptin receptor+ cells promote bone marrow innervation and regeneration by synthesizing nerve growth factor

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