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

Gao, Xiang; Murphy, Malea M.; Peyer, James G.; Ni, Yuehan; Yang, Min; Zhang, Yixuan; Guo, Jiaming; Kara, Nergis; Embree, Claire; Tasdogan, Alpaslan; Ubellacker, Jessalyn M.; Crane, Genevieve M.; Fang, Shentong; Zhao, Zhiyu; Shen, Bo; Morrison, Sean J.

doi:10.1038/s41556-023-01284-9

Cited by 20 publications

(8 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The absolute number of marrow cells markedly decreased after IR and remained low for up to 10 days after lethal IR in C57BL6 mice. Similarly, the frequencies of CAR/Lepr + MSCs decreased to approximately 10% of the non-IR control three days after IR, which is consistent with previous findings [25], and did not recover during our observation period (Fig. 3A and B).…”

Section: Ir-resistant Endogenous Mscs Restrict the Engraftment Of Hmscssupporting

confidence: 92%

Engraftment of human mesenchymal stem cells in a severely immunodeficient mouse

Kato,

Ito,

Taketani

et al. 2024

Preprint

View full text Add to dashboard Cite

The transplantation of human mesenchymal stromal/stem cells (hMSCs) has potential as a curative and permanent therapy for congenital skeletal diseases. However, the self-renewal and differentiation capacities of hMSCs markedly vary. Therefore, cell proliferation and trilineage differentiation capacities were tested in vitro to characterize hMSCs before their clinical use. However, it remains unclear whether the ability of hMSCs in vitro accurately predicts that in living animals. The xenograft model is an alternative method for validating clinical MSCs. Nevertheless, the protocol still needs improvement and it has yet to be established whether hMSCs, which are expanded in culture for clinical use, retain the ability to engraft and differentiate into adipogenic, osteogenic, and chondrogenic lineage cells in transplantation settings. In the present study, to establish a robust xenograft model of MSCs, we examined the delivery routes of hMSCs and the immunological state of recipients. The intra-arterial injection of hMSCs into X-ray-irradiated (IR) NOG, a severely immunodeficient mouse, achieved the highest engraftment, but failed to sustain long-term engraftment. We demonstrated that graft cells localized to a collagenase-released fraction (CR), in which endogenous colony-forming cells reside. We also showed that Pdgfrα+Sca1+ MSCs (PαS), which reside in the CR fraction, resisted IR. These results show that our protocol enables hMSCs to fulfill a high level of engraftment in mouse bone marrow in the short term. In contrast, long-term reconstitution was restricted, at least partially, because of IR-resistant endogenous MSCs.

show abstract

Section: Ir-resistant Endogenous Mscs Restrict the Engraftment Of Hmscssupporting

confidence: 92%

Engraftment of human mesenchymal stem cells in a severely immunodeficient mouse

Kato,

Ito,

Taketani

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…4 e). Alongside vascular endothelium in the BM microenvironment, LEPR + MSCs cooperatively support HSPC function and niche integrity through the expression of hematopoietic-supportive factors [ 34 , 36 – 44 ]. While Bmx-creER T2 efficiently labels BM arterioles, the potential for off-target effects in LEPR + cells should be taken into consideration during experimental design and data interpretation.…”

Section: Resultsmentioning

confidence: 99%

Complementary and Inducible creERT2 Mouse Models for Functional Evaluation of Endothelial Cell Subtypes in the Bone Marrow

Poulos,

Ramalingam,

Winiarski

et al. 2024

Stem Cell Rev and Rep

View full text Add to dashboard Cite

In the adult bone marrow (BM), endothelial cells (ECs) are an integral component of the hematopoietic stem cell (HSC)-supportive niche, which modulates HSC activity by producing secreted and membrane-bound paracrine signals. Within the BM, distinct vascular arteriole, transitional, and sinusoidal EC subtypes display unique paracrine expression profiles and create anatomically-discrete microenvironments. However, the relative contributions of vascular endothelial subtypes in supporting hematopoiesis is unclear. Moreover, constitutive expression and off-target activity of currently available endothelial-specific and endothelial-subtype-specific murine cre lines potentially confound data analysis and interpretation. To address this, we describe two tamoxifen-inducible cre-expressing lines, Vegfr3-creERT2 and Cx40-creERT2, that efficiently label sinusoidal/transitional and arteriole endothelium respectively in adult marrow, without off-target activity in hematopoietic or perivascular cells. Utilizing an established mouse model in which cre-dependent recombination constitutively-activates MAPK signaling within adult endothelium, we identify arteriole ECs as the driver of MAPK-mediated hematopoietic dysfunction. These results define complementary tamoxifen-inducible creERT2-expressing mouse lines that label functionally-discrete and non-overlapping sinusoidal/transitional and arteriole EC populations in the adult BM, providing a robust toolset to investigate the differential contributions of vascular subtypes in maintaining hematopoietic homeostasis. Graphical Abstract

show abstract

“…BMAds and their precursors LepR + stromal cells in adult bone marrow, are the major sources of NGF, KitL and VEGF contributing to sustain nerves and promote haematopoietic and vascular regeneration after myeloablation 17 , 74 . These emerging evidences suggest marrow adipocytes homeostasis are essential, especially in impaired bone marrow environment after irradiation or chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow

Huang,

Lu,

Wang

et al. 2024

Nat Commun

View full text Add to dashboard Cite

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

show abstract

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

Cited by 20 publications

References 64 publications

Engraftment of human mesenchymal stem cells in a severely immunodeficient mouse

Engraftment of human mesenchymal stem cells in a severely immunodeficient mouse

Complementary and Inducible creERT2 Mouse Models for Functional Evaluation of Endothelial Cell Subtypes in the Bone Marrow

Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow

Contact Info

Product

Resources

About