Niche Comparisons Identify PGI2 as a New Means to Support and Protect HSCs

Review of “Prostacyclin is an endosteal bone marrow niche component and its analogue iloprost protects hematopoietic stem cell potential during stress” from STEM CELLS by Stuart P. Atkinson

In their recent STEM CELLS article [1], researchers led by Ingrid G Winkler and Joshua Tay (University of Queensland, Woolloongabba, QLD, Australia) report on their exploration of the differential expression of niche factors supporting the maintenance and activity of hematopoietic stem cells (HSCs) when comparing the bone marrow and the endosteum (the ~twelve-cell diameter from the bone/bone marrow interface) [2-4]. Studies have suggested that HSCs from the endosteum possess more significant long-term competitive repopulation potential than bone marrow-derived HSCs [5, 6] (See the STEM CELLS article for more!), suggesting the existence of tissue-specific niche-derived factors.

Tay et al. searched for novel HSC niche factors by comparing gene expression in endosteal cells and the bone marrow from the femur. Interestingly, this revealed the enriched expression of known HSC supporting factors, such as KITL and CXCL12 in the endosteal compartment, but also the elevated expression of prostacyclin/prostaglandin I2 (PGI2) synthase (PTGIS).

As PGI2 had yet to be described as a regulator of hematopoiesis and HSCs, the authors employed stable analogs of PGI2 to investigate the role of PGI2 in HSC regulation in the endosteal bone marrow niche. Of note, prostacyclin analogs have been safely clinically employed for vascular diseases and can therefore be swiftly repurposed for other therapeutic uses [7]. Their subsequent analysis revealed that the in-vitro treatment of HSCs with PGI2 analogs induced self-renewal and reduced differentiation, which the authors linked to increased signal transducer and activator of transcription 3 (STAT3) signaling and potential alterations in cellular metabolism; furthermore, ex-vivo pulse-treated HSCs displayed long-term competitive repopulation activity after transplantation without having a significant impact on proliferation.

Interestingly, PGI2 analog treatment in vivo failed to impact steady-state hematopoiesis; however, this treatment did function to limit HSC exhaustion induced by sublethal irradiation-mediated stress and granulocyte colony-stimulating factor (G-CSF)-mediated inflammation stress by suppressing niche inflammation and HSC cycling and supporting niche function and HSC homing/survival.

The identification of PGI2 as an HSC-supportive endosteal bone marrow-associated factor that functions at both the cell-intrinsic (via direct intracellular signaling) and cell-extrinsic (niche mediated) level may foster the development of new therapies to support HSC engraftment after autologous transplantation and protect HSCs in patients undergoing radiation or chemotherapy treatment for non-hematologic malignancies.

For more on HSCs, the stem cell niche, and the future exploration of the therapeutic potential of PGI2, stay tuned to the Stem Cells Portal!

References

1. Tay J, Barbier V, Helwani FM, et al., Prostacyclin is an endosteal bone marrow niche component and its clinical analog iloprost protects hematopoietic stem cell potential during stress. STEM CELLS 2021;39:1532-1545.
2. Nombela-Arrieta C, Pivarnik G, Winkel B, et al., Quantitative imaging of haematopoietic stem and progenitor cell localization and hypoxic status in the bone marrow microenvironment. Nature Cell Biology 2013;15:533-543.
3. Acar M, Kocherlakota KS, Murphy MM, et al., Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature 2015;526:126-130.
4. Nilsson SK, Dooner MS, Tiarks CY, et al., Potential and Distribution of Transplanted Hematopoietic Stem Cells in a Nonablated Mouse Model. Blood 1997;89:4013-4020.
5. Haylock DN, Williams B, Johnston HM, et al., Hemopoietic Stem Cells with Higher Hemopoietic Potential Reside at the Bone Marrow Endosteum. STEM CELLS 2007;25:1062-1069.
6. Grassinger J, Haylock DN, Williams B, et al., Phenotypically identical hemopoietic stem cells isolated from different regions of bone marrow have different biologic potential. Blood 2010;116:3185-3196.
7. Pluchart H, Khouri C, Blaise S, et al., Targeting the Prostacyclin Pathway: Beyond Pulmonary Arterial Hypertension. Trends in Pharmacological Sciences 2017;38:512-523.