Combining Growth Factor and Bone Marrow Cell Therapy Induces Bleeding and Alters Immune Response After Stroke in Mice

Abstract

Background and Purpose-Bone marrow cell (BMC)-based therapies, either the transplantation of exogenous cells or stimulation of endogenous cells by growth factors like the granulocyte colony-stimulating factor (G-CSF), are considered a promising means of treating stroke. In contrast to large preclinical evidence, however, a recent clinical stroke trial on G-CSF was neutral. We, therefore, aimed to investigate possible synergistic effects of co-administration of G-CSF and BMCs after experimental stroke in mice to enhance the efficacy compared with single treatments. Methods-We used an animal model for experimental stroke as paradigm to study possible synergistic effects of co-administration of G-CSF and BMCs on the functional outcome and the pathophysiological mechanism. Results-G-CSF treatment alone led to an improved functional outcome, a reduced infarct volume, increased blood vessel stabilization, and decreased overall inflammation. Surprisingly, the combination of G-CSF and BMCs abrogated G-CSFs' beneficial effects and resulted in increased hemorrhagic infarct transformation, altered blood-brain barrier, excessive astrogliosis, and altered immune cell polarization. These increased rates of infarct bleeding were mainly mediated by elevated matrix metalloproteinase-9-mediated blood-brain barrier breakdown in G-CSF-and BMCs-treated animals combined with an increased number of dilated and thus likely more fragile vessels in the subacute phase after cerebral ischemia. Conclusions-Our results provide new insights into both BMC-based therapies and immune cell biology and help to understand potential adverse and unexpected side effects.

Combining Human Umbilical Cord Blood Cells With Erythropoietin Enhances Angiogenesis/Neurogenesis and Behavioral Recovery After Stroke

“…However, not all trials were successful. A recent study revealed potential side effects that are harmful in ischemic stroke when hBMSC were transplanted with granulocyte colony-stimulating factor, leading to findings of increased hemorrhagic transformation and astrogliosis with alterations in the blood-brain barrier (46). In the present study, the results seem to show an additive or synergistic effect of combined treatment with hUCBC and EPO, without a diluting effect, both for neurogenesis and angiogenesis.…”

Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke

“…By modulating the inflammatory processes, transplanted cells increase their own chances of survival. Otherwise, such processes can result in failure to survive or engraft, bleeding, altered immune responses and can reduce or even eliminate the therapeutic effects of transplantation (Strecker et al, 2016). …”

Dietary salt promotes ischemic brain injury and is associated with parenchymal migrasome formation

“…Seventy-two adult male C57BL/6 mice received either high-salt diet containing 4% NaCl (ssniff, Germany) and tap water containing 1% NaCl ad libitum (high-salt, n = 36) or standard diet and tap water ad libitum (standard, n = 36), as previously described [3,4]. Seven days after the initiation of high-salt diet, ischemic stroke was induced by transient middle cerebral artery occlusion (MCAO) as previously described [15,16]. To evaluate whether high-salt diet had an impact on functional outcomes, neurological deficit score assessment was performed according to a modification of Menzies neuroscore [15], which showed significantly worse outcomes following high-salt diet (p<0.05, 2way ANOVA, Fig 1A).…”

“…The total number of F4/80 + -microglia/macrophages was significantly reduced after high-salt diet (p<0.01, t-test, Fig 2B). In particular, the number of cells expressing Arginase-1, an exemplary marker for anti-inflammatory microglia/macrophages [16,19], was reduced following high-salt diet (p<0.05, t-test, Fig 2C). CD16/32 + -cells, indicating pro-inflammatory microglia/macrophages [19,20], were unaltered (p = 0.28, t-test, Fig 2C).…”