Primary cilia are present on human blood and bone marrow cells and mediate Hedgehog signaling

Singh, Mohan; Chaudhry, Parvesh; Merchant, Akil

doi:10.1016/j.exphem.2016.08.009

Cited by 45 publications

(39 citation statements)

References 19 publications

(22 reference statements)

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“…Lymphocytes are usually considered as a classical example of non-ciliated cells [10,11], although some contradicting studies were published [62,63]. Importantly, T cells repurpose a number of proteins associated with the ciliary transport for the formation of the immunological synapse.…”

Section: Discussionmentioning

confidence: 99%

Altered hematopoietic system and self-tolerance in Bardet-Biedl Syndrome

Tsyklauri

Niederlová

Forsythe

et al. 2020

Preprint

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Bardet-Biedl Syndrome (BBS) is a pleiotropic genetic disease caused by dysfunction of primary cilia. The immune system of patients with BBS or another ciliopathy has not been investigated, most likely because hematopoietic cells do not form cilia. However, there are multiple indications that the impairment of the processes typically associated with cilia might influence the hematopoietic compartment and immunity. In this study, we analyzed clinical data of BBS patients as well as a corresponding mouse model of BBS4 deficiency. We uncovered that BBS patients have higher incidence of certain autoimmune diseases. BBS patients and animal models have elevated white blood cell levels and altered red blood cell and platelet compartments. Moreover, we observed that BBS4 deficiency alters the development and homeostasis of B cells in mice. Some of the hematopoietic system alterations were caused by the BBS-induced obesity.Overall, our study reveals a connection between a ciliopathy and the alterations of the immune system and the hematopoietic compartment.

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Section: Discussionmentioning

confidence: 99%

Altered hematopoietic system and self-tolerance in Bardet-Biedl Syndrome

Tsyklauri

Niederlová

Forsythe

et al. 2020

Preprint

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“…In normal tissue, Hh activation is dependent on the transmembrane protein Smoothened (SMO) . Hh ligand‐binding results in the Patched receptor releasing SMO, which then moves from an intracellular vesicle into the primary cilium . Activated glioma (GLI)‐associated proteins then translocate to the nucleus and promote target gene transcription .…”

Section: Introductionmentioning

confidence: 99%

“…Hh ligand‐binding results in the Patched receptor releasing SMO, which then moves from an intracellular vesicle into the primary cilium . Activated glioma (GLI)‐associated proteins then translocate to the nucleus and promote target gene transcription . Aberrations in Hh signaling have been identified in a variety of human leukemias and particularly in leukemia stem cells .…”

Section: Introductionmentioning

confidence: 99%

Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high‐risk MDS: Phase 2 study results

et al. 2018

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Glasdegib is a Hedgehog pathway inhibitor. This ongoing, open‐label, phase 2 study (NCT01546038) evaluated glasdegib plus cytarabine/daunorubicin in patients with untreated acute myeloid leukemia (AML) or high‐risk myelodysplastic syndromes (MDS). Patients received glasdegib 100 mg orally, once daily in continuous 28‐day cycles from day −3, with intravenous cytarabine 100 mg/m2 on days 1‐7 and daunorubicin 60 mg/m2 on days 1‐3. Patients in remission then received consolidation therapy (2‐4 cycles of cytarabine 1 g/m2 twice daily on days 1, 3, 5 of each cycle), followed by maintenance glasdegib (maximum 6 cycles). Primary endpoint was complete remission (CR) in patients aged ≥55 years. Secondary endpoints included overall survival (OS), safety and outcome by mutational status. Patients had a median (range) age of 64.0 (27‐75) years, 60.0% were male, and 84.5% were white. In 69 evaluable patients, 46.4% (80% confidence interval [CI]: 38.7‐54.1) achieved investigator‐reported CR. Among patients ≥55 years old (n = 60), 40.0% (80% CI 31.9‐48.1) achieved CR. Among all 69 patients, median OS was 14.9 (80% CI 13.4‐19.3) months, with 12‐month survival probability 66.6% (80% CI 58.5‐73.4). The most common treatment‐related adverse events (≥50% patients) were diarrhea and nausea. There were no significant associations between mutational status (12 genes) and clinical response, suggesting potential benefit across diverse molecular profiles. Glasdegib plus cytarabine/daunorubicin was well tolerated and associated with clinical activity in patients with untreated AML or high‐risk MDS. A randomized phase 3 trial of glasdegib in combination with chemotherapy (7 + 3 schedule) is ongoing.

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“…First, primary cilia are present on a variety of different cells, including cells of the hematopoietic lineage. 65 Fluid flow stimulation in vitro deflects primary cilia on osteocytes, which causes an immediate rise in cytosolic Ca 2+ . 66,67 This initial rise in intracellular Ca 2+ is amplified by the release of ATP and the subsequent purinergic response through P2X and P2Y receptors.…”

Section: Discussionmentioning

confidence: 99%

High shear stress amplitude in combination with prolonged stimulus duration determine induction of osteoclast formation by hematopoietic progenitor cells

et al. 2020

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To date, it is unclear how fluid dynamics stimulate mechanosensory cells to induce an osteoprotective or osteodestructive response. We investigated how murine hematopoietic progenitor cells respond to 2 minutes of dynamic fluid flow stimulation with a precisely controlled sequence of fluid shear stresses. The response was quantified by measuring extracellular adenosine triphosphate (ATP), immunocytochemistry of Piezo1, and sarcoplasmic/endoplasmic Ca2+ reticulum ATPase 2 (SERCA2), and by the ability of soluble factors produced by mechanically stimulated cells to modulate osteoclast differentiation. We rejected our initial hypothesis that peak wall shear stress rate determines the response of hematopoietic progenitor cells to dynamic fluid shear stress, as it had only a minor correlation with the abovementioned parameters. Low stimulus amplitudes corresponded to activation of Piezo1, SERCA2, low concentrations of extracellular ATP, and inhibition of osteoclastogenesis and resorption area, while high amplitudes generally corresponded to osteodestructive responses. At a given amplitude (3 Pa) and waveform (square), the duration of individual stimuli (duty cycle) showed a strong correlation with the release of ATP and osteoclast number and resorption area. Collectively, our data suggest that hematopoietic progenitor cells respond in a viscoelastic manner to loading, since a combination of high shear stress amplitude and prolonged duty cycle is needed to trigger an osteodestructive response. Plain Language Summary In case of painful joints or missing teeth, the current intervention is to replace them with an implant to keep a high‐quality lifestyle. When exercising or chewing, the cells in the bone around the implant experience mechanical loading. This loading generally supports bone formation to strengthen the bone and prevent breaking, but can also stimulate bone loss when the mechanical loading becomes too high around orthopedic and dental implants. We still do not fully understand how cells in the bone can distinguish between mechanical loading that strengthens or weakens the bone. We cultured cells derived from the bone marrow in the laboratory to test whether the bone loss response depends on (i) how fast a mechanical load is applied (rate), (ii) how intense the mechanical load is (amplitude), or (iii) how long each individual loading stimulus is applied (duration). We mimicked mechanical loading as it occurs in the body, by applying very precisely controlled flow of fluid over the cells. We found that a mechanosensitive receptor Piezo1 was activated by a low amplitude stimulus, which usually strengthens the bone. The potential inhibitor of Piezo1, namely SERCA2, was only activated by a low amplitude stimulus. This happened regardless of the rate of application. At a constant high amplitude, a longer duration of the stimulus enhanced the bone‐weakening response. Based on these results we deduce that a high loading amplitude tends to be bone weakening, and the longer this high amplitude persists, the wor...

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Primary cilia are present on human blood and bone marrow cells and mediate Hedgehog signaling

Cited by 45 publications

References 19 publications

Altered hematopoietic system and self-tolerance in Bardet-Biedl Syndrome

Altered hematopoietic system and self-tolerance in Bardet-Biedl Syndrome

Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high‐risk MDS: Phase 2 study results

High shear stress amplitude in combination with prolonged stimulus duration determine induction of osteoclast formation by hematopoietic progenitor cells

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