Dental Pulp Stem Cell-Derived Factors Alleviate Subarachnoid Hemorrhage-Induced Neuroinflammation and Ischemic Neurological Deficits

Abstract

Aneurysmal subarachnoid hemorrhage (aSAH), characterized by the extravasation of blood into the subarachnoid space caused by an intracranial aneurysm rupture, may lead to neurocognitive impairments and permanent disability and usually carries poor outcome. Dental or gingiva-derived stem cells have been shown to contribute to immune modulation and neuroregeneration, but the underlying mechanisms are unclear. In the present study, we sought to investigate whether dental pulp stem cells (DPSCs) secrete certain factor(s) that can ameliorate the neural damage and other manifestations in a rat aSAH model. Twenty-four hours after the induction of aSAH, microthrombosis, cortical vasoconstriction, and the decrease in microcirculation and tissue oxygen pressure were detected. Intrathecal administration of DPSC-derived conditioned media (DPSC-CM) ameliorated aSAH-induced vasoconstriction, neuroinflammation, and improved the oxygenation in the injured brain. Rotarod test revealed that the aSAH-induced cognitive and motor impairments were significantly improved by this DPSC-CM administration. Cytokine array indicated the major constituent of DPSC-CM was predominantly insulin growth factor-1 (IGF-1). Immunohistochemistry staining of injured brain tissue revealed the robust increase in Iba1-positive cells that were also ameliorated by DPSC-CM administration. Antibody-mediated neutralization of IGF-1 moderately deteriorated the rescuing effect of DPSC-CM on microcirculation, Iba1-positive cells in the injured brain area, and the cognitive/motor impairments. Taken together, the DPSC-derived secretory factors showed prominent therapeutic potential for aSAH. This therapeutic efficacy may include improvement of microcirculation, alleviation of neuroinflammation, and microglial activation; partially through IGF-1-dependent mechanisms.

Dental Stem Cell-Derived Secretome/Conditioned Medium: The Future for Regenerative Therapeutic Applications

“…Collectively, these data clearly demonstrated that dental pulp MSC-CM harbors an array of neuroprotective and angiogenic factors such as NGF, BDNF and VEGF [66], RANTES, fractalkine, FLT-3, GM-CSF, MCP-1, and neprilysin [148], besides IGF-1, TGF-β, TIMP-1, and TIMP-2 [151], which account for their promising abilities to induce tissue regeneration in many neurological diseases. (Table 4).…”

“…Intrathecal administration of dental pulp MSC-CM in a rat aneurysmal subarachnoid hemorrhage model revealed improvement in cognitive and motor impairments, microcirculation, and reduction of neuroinflammation. IGF-1, TGF-β, tissue inhibitor of metalloproteinase-(TIMP-) 1, and TIMP-2 were identified as significant components in dental pulp MSC-CM that contribute to these improvements [151].…”

“…Several studies supported the neuroregenerative effects of dental MSC-CM [66,69,109,110,112,116,[168][169][170]173]. The key role of dental MSC-CM as a modulator of the neurogenic microenvironment is through the release of multiple growth factors promoting neural growth and differentiation like NGF [65,66,110,117]; BDNF [65, 66, 110, 117, 168-170, 173, 176]; NT-3 [65, 110, 168-170, 173, 176]; CNTF, GDNF, and HGF [110]; IGF [117,151]; MFI, MAP-2, β-tubulin III, nestin, and SOX-1 [65], besides Neurofilament 200 and S100 [168][169][170]173].…”

Dental Pulp Stem Cells on Implant Surface: An In Vitro Study

“…Stem cells are found in various body tissues: blood, muscles, skin, bone marrow, nerves, and liver. The key property of all stem cells is that they are undifferentiated; therefore, they can replicate indefinitely and replace/renew different types of damaged cells in the body [1][2][3][4]. Stem cells can divide and replicate over 200 types of specialized cells that are linked to the function of the immune system, heart, oxygen distribution, and others.…”

Effects of clazosentan, cilostazol, and statins on aneurysmal subarachnoid hemorrhage

“…Aneurysmal subarachnoid hemorrhage (aSAH) is a disease caused by the infiltration of blood into the subarachnoid space due to the rupture of an intracranial aneurysm. [ 1 ] It is a severe cerebrovascular disease, accounting for 5% of all strokes. [ 2 , 3 ] Aneurysmal subarachnoid hemorrhage often causes many complications, such as cerebral ischemia, vasospasm, bacterial meningitis, cephaledema, hydrocephalus, and seizure.…”