Safety of Intraparenchymal Injection of Allogenic Placenta Mesenchymal Stem Cells Derived Exosome in Patients Undergoing Decompressive Craniectomy Following Malignant Middle Cerebral Artery Infarct, A Pilot Randomized Clinical Trial

Leila Dehghani, Arash Khojasteh, Masoud Soleimani, Saeed Oraee‑Yazdani, Saeed Heidari Keshel, Mohammad Saadatnia, Masih Saboori, Alireza Zali, Seyed Mahmoud Hashemi, Reyhane Soleimani

Abstract


Background: Malignant middle cerebral artery infarct (mMCAI) largely contributes to high mortality and physical disability among adults. Surviving individuals may not have proper outcomes and suffer from severe lasting disabilities. Utilization of stem cells and paracrine factor for regenerative purposes is considered as a potential strategy for patients with neurological deficits. While preclinical stroke studies have shown that mesenchymal stem cells (MSCs) reduce post‑treatment neurological deficits and prevent disability and also promote recovery, few randomized clinical trials (RCT) have assessed exosome therapy in humans.

Methods: In this RCT, we assessed the safety of intraparenchymal injection placenta MSC‑derived Exosome in mMCAI patients with average age of 62 years between January, 2019, till September, 2020. The study was done in a single‑center as an open‑label RCT, with a 3‑months follow‑up. Primary outcomes assessed the safety and also disability indexes were followed.

Results: Five mMCAI patients were included with mean NIHSS: 17.6 ± 5.02. The mean MRS was 3.25 ± 0.95 in three patients. No serious adverse events were observed. Hematoma or local reaction as excessive edema were not seen at the site of injection.

Conclusions: Intraparenchymal implantation of MSC‑EXO showed no post‑interventional adverse effects in five ischemic stroke patients. It is proposed Local injection Exosome treatment following mMCAI can be safe and in future, it would be applied as a supportive, restorative and preventive treatment in patients who suffer from acute ischemic stroke and post ischemic disability


Keywords


Allogenic mesenchymal stem cell; decompressive craniectomy; exosome; mMCAI

Full Text:

PDF

References


Treadwell SD, Thanvi B. Malignant Middle cerebral

artery (MCA) infarction: Pathophysiology, diagnosis and

management. Postgrad Med J 2010;86:235‑42.

Lammy S, Al‑Romhain B, Osborne L, George EJS. 10‑year

institutional retrospective case series of decompressive

craniectomy for malignant middle cerebral artery

infarction (mMCAI). World Neurosurg 2016;96:383‑9.

Hatefi D, Hirshman B, Leys D, Lejeune J‑P, Marshall L,

Carter BS, et al. Hemicraniectomy in the management of

malignant middle cerebral artery infarction: Lessons from

randomized, controlled trials. Surg Neurol Int 2014;5:72.

Vahedi K, Hofmeijer J, Juettler E, Vicaut E, George B, Algra A,

et al. Early decompressive surgery in malignant infarction of the

middle cerebral artery: A pooled analysis of three randomised

controlled trials. Lancet Neurol 2007;6:215‑22.

Gupta R, Connolly ES, Mayer S, Elkind MS. Hemicraniectomy

for massive middle cerebral artery territory infarction:

A systematic review. Stroke 2004;35:539‑43.

Das S, Mitchell P, Ross N, Whitfield PC. Decompressive

hemicraniectomy in the treatment of malignant middle

cerebral artery infarction: A meta‑analysis. World Neurosurg

;123:8‑16.

Peplow PV, Martinez B, Mascareñas D, Dambinova SA.

Neuroplasticity biomarkers in experimental stroke recovery.

Stroke Biomarkers. Springer; 2020. p. 35‑59.

Otero‑Ortega L, Laso‑García F, del Carmen Gómez‑de Frutos M,

Rodríguez‑Frutos B, Pascual‑Guerra J, Fuentes B, et al. White

matter repair after extracellular vesicles administration in an

experimental animal model of subcortical stroke. Sci Rep

;7:44433.

Zivin JA. Acute stroke therapy with tissue plasminogen

activator (tPA) since it was approved by the U.S. Food and drug

administration (FDA). Ann Neurol 2009;66:6‑10.

Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD,

Andriantsitohaina R, et al. Minimal information for studies

of extracellular vesicles 2018 (MISEV2018): A position

statement of the International society for extracellular vesicles

and update of the MISEV2014 guidelines. J Extracell Vesicles

;7:1535750.

Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L,

Yassi N, et al. Endovascular therapy for ischemic stroke with

perfusion‑imaging selection. N Engl J Med 2015;372:1009‑18.

Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and

opportunities in stroke. Nat Rev Neurosci 2003;4:399‑414.

Zhang ZG, Buller B, Chopp M. Exosomes — Beyond stem cells

for restorative therapy in stroke and neurological injury. Nat Rev

Neurol 2019;15:193‑203.

Adeoye O, Hornung R, Khatri P, Kleindorfer D. Recombinant

tissue‑type plasminogen activator use for ischemic stroke in the

United States: A doubling of treatment rates over the course of

years. Stroke 2011;42:1952‑5.

Dehghani L, Hashemi SM, Saadatnia M, Zali A,

Oraee‑Yazdani S, Keshel SH, et al. Stem cell‑derived exosomes

as treatment for stroke: A systematic review. Stem Cell Rev Rep

;17:428‑38.

Chen K‑H, Chen C‑H, Wallace CG, Yuen C‑M, Kao G‑S,

Chen Y‑L, et al. Intravenous administration of xenogenic

Adipose‑derived mesenchymal stem cells (ADMSC) and

ADMSC‑derived exosomes markedly reduced brain infarct

volume and preserved neurological function in rat after acute

ischemic stroke. Oncotarget 2016;7:74537‑56.

Ikegame Y, Yamashita K, Hayashi S‑I, Mizuno H, Tawada M,

You F, et al. Comparison of mesenchymal stem cells from

adipose tissue and bone marrow for ischemic stroke therapy.

Cytotherapy 2011;13:675‑85.

Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A,

Petticrew M, et al. Preferred reporting items for systematic

review and meta‑analysis protocols (PRISMA‑P) 2015 statement.

Syst Rev 2015;4:1.

Kean TJ, Lin P, Caplan AI, Dennis JE. MSCs: Delivery

routes and engraftment, cell‑targeting strategies, and immune

modulation. Stem Cells Int 2013;2013:Article ID 732742, 13

pages. doi: 10.1155/2013/732742.

Dehghani L, Khojasteh A, Oraee YS, Oustad M, Soleimani M.

Role of mesenchymal stem cells derived exosomes therapy in

neuronal remodeling after ischemic stroke. Minerva Med 2019.

doi: 10.23736/S0026‑4806.19.06277‑3.

Chen SY, Lin Mc, Tsai JS, He PL, Luo WT, Chiu IM, et al.

Exosomal 2′,3′‑CNP from mesenchymal stem cells promotes

hippocampus CA1 neurogenesis/neuritogenesis and contributes to rescue of cognition/learning deficiencies of damaged brain.

Stem Cells Transl Med 2020;9:499‑517.

Doeppner TR, Herz J, Görgens A, Schlechter J, Ludwig A‑K,

Radtke S, et al. Extracellular vesicles improve post‑stroke

neuroregeneration and prevent postischemic immunosuppression.

Stem Cells Transl Med 2015;4:1131‑43.

Ueno Y, Hira K, Miyamoto N, Kijima C, Inaba T, Hattori N.

Pleiotropic effects of exosomes as a therapy for stroke recovery.

Int J Mol Sci 2020;21:6894.

Otero‑Ortega L, Gutiérrez‑Fernández M, Ramos‑Cejudo J,

Rodríguez‑Frutos B, Fuentes B, Sobrino T, et al. White matter

injury restoration after stem cell administration in subcortical

ischemic stroke. Stem Cell Res Ther 2015;6:121.

Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M. Systemic

administration of exosomes released from mesenchymal

stromal cells promote functional recovery and neurovascular

plasticity after stroke in rats. J Cereb Blood Flow Metab

;33:1711‑5.