Stroke treatment using umbilical cord stem cells

Stroke can lead to death or permanent disability, debilitate the human body, impaired mobility and cognition, and leave a tremendous burden on the patient’s family and society [1]. Initial intervention measures such as surgery and the use of special medicines have had certain effectiveness. However, long-term intervention may still be required, even lifelong treatment. After surgery, rehabilitation is still needed to help patients improve their memory and motor skills. One of the potential ways to improve patient health is to use mesenchymal stem cells through their neuroprotective mechanisms and ability to reduce inflammation after stroke [2]. While still in the process of development and improvement, stem cell therapy is considered a new stroke treatment that may improve neurological recovery.

Medicines and surgical intervention in stroke treatment

Stroke is the phenomenon of sudden death of brain cells in a specific area because of interrupted blood flow. It is one of the most common causes of death after cancer and myocardial infarction and mainly occurs in older adults population, with a higher risk in men. Normal brain function will end if hypoxia exceeds 60-90 seconds and brain tissue dies within 3 hours after hypoxia, leading to cerebral infarction [3]. Therefore, immediate intervention is important in maintaining the patient’s life. Common ways of treatment include using special medicines (anticoagulants, antiplatelet drugs) or surgical intervention (re-clot removal surgery, decompression surgery) [4].

Both tissue activators and surgical intervention have a certain period, known as the “golden window,” to prevent damage effectively and contribute to neurological recovery [5]. Currently, researchers need new stroke treatments to overcome the obstacles posed by the narrow time window and lack of restorative benefits in intracerebral hemorrhage [5,6]. Stem cell therapy is one method that brings good recovery to stroke patients.

Stem cell therapy in stroke treatment

Stem cell-based therapies aim to promote neurogenesis, replace or restore lost neurons, or protect surviving neurons to improve neurological recovery. The mechanism by which stem cell treatments mediate their therapeutic effects largely depends on the stem cell type and route of administration. Mesenchymal stem cells (MSCs) are pluripotent stem cells capable of self-renewal and can differentiate into different cell types. MSCs are prevalent in many tissues outside the bone marrow, including adipose tissue, lung tissue, and endometrium [7]. Currently, researchers mainly use MSCs derived from bone marrow, adipose tissue, and umbilical cord blood in clinical studies. Stem cells are transplanted during the acute, subacute, or chronic phase of ischemic stroke.

In the studies, researchers administered adipose-derived donor MSCs intravenously to 400 patients 14 days after an ischemic stroke. Neurological function improved without side effects after stem cell transplantation [8,9]. Intrathecal injection is used to transplant stem cell doses ranging from 2 to 20 million cells/kg body weight into the patient’s cerebral hemisphere. The medical team then monitors the patients from 6 to 60 months after ischemic stroke. Within two years after treatment, it brought positive effects to patients [10].

Application of umbilical cord stem cells in the treatment of brain injury and stroke

Umbilical cord mesenchymal stem cells (UC-MSCs) have multi-lineage differentiation, endocrine function, and immunomodulatory properties. In addition, there is no need for bone marrow aspiration, and the ability to regenerate the self-regenerate of UC-MSCs is higher. UC-MSCs reduce neuronal cell death by increasing the expression of gliotrophic factors and reducing the number of macrophages, inducing a neuroprotective effect [11]. Methods of delivering UC-MSCs for brain injury include lumbar puncture, arterial and intravenous infusion, direct injection into the brain, and implantation of biomaterials. When infusing UC-MSCs through intravenous injection, it is important to optimize the number of cells to prevent them from getting trapped in the lungs and unable to migrate to the brain or other organs. Arterial infusion provides a relatively wider distribution in the body than intravenous infusion. Intravenous infusion is simple and minimally invasive and has few side effects. Surgical and anesthetic risks are limited, as providing control measures for injecting stem cells into desired locations is difficult. The therapeutic effect of combining UC-MSC with other drugs or adjuvant therapy produces better results than a single therapy. For example, UC-MSC transplantation combined with minimally invasive phlebotomy for cerebral hemorrhage or combined with lead drugs for radiation-induced brain injury has shown superior treatment efficacy compared to therapy using only UC-MSCs [12].

The process of cell proliferation and distribution, the delivery method (whether the cells are injected or infused), and the efficiency of injected cells migrating to the affected sites are all crucial factors in achieving the highest effectiveness in stroke treatment. Criteria for providing cell products for commercial and clinical applications of stem cells with cryopreservation procedures for long-term storage, ensuring stem cell properties. Proliferation time and cell culture, including substrates and clinical reagents, may induce MSCs to differ in their immunomodulatory properties, influencing the therapeutic efficacy of the cells.

Prospects of stem cell therapy in stroke treatment

Stroke remains the most common cause of death related to brain diseases in developed countries, thus requiring serious attention through the conduct of preclinical studies in both acute and chronic phases. Ischemic stroke, which causes acute neuroinflammation that can worsen the initial brain injury. Most current clinical trials aim to measure the safety and feasibility of using different human adult stem cells in stroke patients and aim to determine the maximum dose. MSCs have similarly been safe but show limited improvements for patients. Although exploration remains, stem cell treatments for stroke may provide ways to protect neurons to improve patient outcomes. Researchers are still working hard to establish a common set of worldwide standards for treating stroke with stem cells, specifically umbilical cord blood stem cells.

References

1. Cramer, Steven C. “Repairing the human brain after stroke: I. Mechanisms of spontaneous recovery.” Annals of neurology63, no. 3 (2008): 272-287.
2. Boncoraglio, Giorgio B., Michela Ranieri, Anna Bersano, Eugenio A. Parati, and Cinzia Del Giovane. “Stem Cell Transplantation for Ischemic Stroke.” Stroke51, no. 1 (2020): e1-e2.
3. Reis, Cesar, Michael Wilkinson, Haley Reis, Onat Akyol, Vadim Gospodarev, Camila Araujo, Sheng Chen, and John H. Zhang. “A look into stem cell therapy: exploring the options for treatment of ischemic stroke.” Stem cells international2017 (2017).
4. Liu, Xinfeng. “Beyond the time window of intravenous thrombolysis: standing by or by stenting?.” Interventional neurology1, no. 1 (2012): 3-15.
5. Doberstein, Cody A., Radmehr Torabi, Sandra C. Yan, Ryan McTaggart, Curtis Doberstein, and Mahesh Jayaraman. “Current strategies in the surgical management of ischemic stroke.” Rhode Island medical journal100, no. 6 (2017): 25.
6. Hemphill III, J. Claude, Steven M. Greenberg, Craig S. Anderson, Kyra Becker, Bernard R. Bendok, Mary Cushman, Gordon L. Fung et al. “Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.” Stroke46, no. 7 (2015): 2032-2060.
7. Jiang, Yuehua, Balkrishna N. Jahagirdar, R. Lee Reinhardt, Robert E. Schwartz, C. Dirk Keene, Xilma R. Ortiz-Gonzalez, Morayma Reyes et al. “Pluripotency of mesenchymal stem cells derived from adult marrow.” Nature418, no. 6893 (2002): 41-49.
8. Díez-Tejedor, Exuperio, María Gutiérrez-Fernández, Patricia Martínez-Sánchez, Berta Rodríguez-Frutos, Gerardo Ruiz-Ares, Manuel Lara Lara, and Blanca Fuentes Gimeno. “Reparative therapy for acute ischemic stroke with allogeneic mesenchymal stem cells from adipose tissue: a safety assessment: a phase II randomized, double-blind, placebo-controlled, single-center, pilot clinical trial.” Journal of Stroke and Cerebrovascular Diseases23, no. 10 (2014): 2694-2700.
9. Jiang, Yongjun, Wusheng Zhu, Juehua Zhu, Li Wu, Gelin Xu, and Xinfeng Liu. “Feasibility of delivering mesenchymal stem cells via catheter to the proximal end of the lesion artery in patients with stroke in the territory of the middle cerebral artery.” Cell Transplantation22, no. 12 (2013): 2291-2298.
10. Kalladka, Dheeraj, John Sinden, Kenneth Pollock, Caroline Haig, John McLean, Wilma Smith, Alex McConnachie et al. “Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study.” The Lancet388, no. 10046 (2016): 787-796.
11. Lin, Willie, Yogi Chang-Yo Hsuan, Mao-Tsun Lin, Ting-Wei Kuo, Cheng-Hsien Lin, Yu-Chin Su, Ko-Chi Niu, Ching-Ping Chang, and Hung-Jung Lin. “Human umbilical cord mesenchymal stem cells preserve adult newborn neurons and reduce neurological injury after cerebral ischemia by reducing the number of hypertrophic microglia/macrophages.” Cell Transplantation26, no. 11 (2017): 1798-1810.
12. Wang, Gui-Hua, Yang Liu, Xiao-Bing Wu, Ying Lu, Jin Liu, Ya-Ru Qin, Tong Li, and Hai-Feng Duan. “Neuroprotective effects of human umbilical cord–derived mesenchymal stromal cells combined with nimodipine against radiation-induced brain injury through inhibition of apoptosis.” Cytotherapy18, no. 1 (2016): 53-64.