Department of Microbiology/Immunology, Indiana University School of Medicine, 950 West Walnut Street, R2 Bldg., Room 302, Indianapolis, IN, 46202-5181, USA.
Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, USA.
Stem Cell Rev Rep. 2022 Oct;18(7):2513-2521. doi: 10.1007/s12015-021-10306-8. Epub 2022 Mar 9.
Little is known about a regulatory role of CaMKK2 for hematopoietic stem (HSC) and progenitor (HPC) cell function. To assess this, we used Camkk2-/- and wild type (WT) control mouse bone marrow (BM) cells. BM cells were collected/processed and compared under hypoxia (3% oxygen; physioxia) vs. ambient air (~21% oxygen). Subjecting cells collected to ambient air, even for a few minutes, causes a stress that we termed Extra Physiological Shock/Stress (EPHOSS) that causes differentiation of HSCs and HPCs. We consider physioxia collection/processing a more relevant way to assess HSC/HPC numbers and function, as the cells remain in an oxygen tension closer physiologic conditions. Camkk2-/- cells collected/processed at 3% oxygen had positive and negative effects respectively on HSCs (by engraftment using competitive transplantation with congenic donor and competitor cells and lethally irradiated congenic recipient mice), and HPCs (by colony forming assays of CFU-GM, BFU-E, and CFU-GEMM) compared to WT cells processed in ambient air. Thus, with cells collected/processed under physioxia, and therefore never exposed and naïve to ambient air conditions, CaMKK2 not only appears to act as an HSC to HPC differentiation fate determinant, but as we found for other intracellular mediators, the Camkk-/- mouse BM cells were relatively resistant to effects of EPHOSS. This information is of potential use for modulation of WT BM HSCs and HPCs for future clinical advantage.
关于 CaMKK2 对造血干细胞（HSC）和祖细胞（HPC）功能的调节作用知之甚少。为了评估这一点，我们使用了 Camkk2-/- 和野生型（WT）对照小鼠骨髓（BM）细胞。在低氧（3%氧气；低氧）与环境空气（~21%氧气）下收集/处理 BM 细胞，并进行比较。即使将细胞暴露在环境空气中几分钟，也会造成一种应激，我们称之为额外生理冲击/应激（EPHOSS），导致 HSCs 和 HPCs 的分化。我们认为低氧收集/处理是一种更相关的方法来评估 HSC/HPC 的数量和功能，因为细胞仍然处于接近生理条件的氧气张力下。与在环境空气中处理的 WT 细胞相比，在 3%氧气下收集/处理的 Camkk2-/-细胞分别对 HSCs（通过与同基因供体和竞争细胞进行竞争移植，并使用致死性辐照同基因受体小鼠进行植入）和 HPCs（通过 CFU-GM、BFU-E 和 CFU-GEMM 的集落形成测定）产生了积极和消极的影响。因此，在用低氧收集/处理的细胞中，由于从未暴露于环境空气条件下，并且是幼稚的，CaMKK2 不仅似乎作为 HSC 到 HPC 分化命运的决定因素起作用，而且正如我们对其他细胞内介质所发现的那样，Camkk-/- 小鼠 BM 细胞对 EPHOSS 的影响相对具有抗性。这些信息对于调节 WT BM HSCs 和 HPCs 以获得未来的临床优势具有潜在的应用价值。
