STEM CELL

pada Neurotrauma
Prof. Dr. dr. Syahrul, Sp. N(K)
Departemen Neurologi, Fakultas Kedokteran Universitas Syiah Kuala
RSUD dr. Zainoel Abidin Banda Aceh
Makassar Neurorestorasi Update - MAKNA 2023
9 September 2023
 TBI Traumatic Brain Injury
The main cause of injury-related deaths,
Disabilities throughout the world,
Characterized by a disruption of the normal
physiology of the brain following trauma
USA,
30% of all injury-related
deaths are due to TBI
Classification of TBIàGCS
Mild : 13 – 15
Moderate : 9 – 12
Severe. :3 - 8
 Neuroimaging Pattern

Bifrontal hemorrhagic Axonal Injury Enlarging hemorrhagic EDH

contusions, frontal bilateral frontal &
Epidural Hematoma
SDHs, diffuse brain temporal lobe contusions
swelling, SAH t
TBI
• The leading cause of disability and mortality in children
and young adults
• A profound impact on the socio-economic wellbeing of
patients and their families
• Brain damage cause by mechanical stress induced:
• axonal injury
• vascular dysfunction
• hemorrhage
• blood brain barrier disruption
• ischemia
TBI Antioxidants 2020, 9, 297
• A major cause of death among youth in industrialized societies
• Brain damage following traumatic injury is a result of direct and
indirect mechanisms :
• indirect or secondary injury involves the initiation of an acute
inflammatory response,
• including the breakdown of the blood–brain barrier (BBB), brain
edema, infiltration of peripheral blood cells, and activation of
resident immunocompetent cells, as well as the release of
numerous immune mediators such as interleukins and
chemotactic factors
• TBI can cause changes in molecular signaling and cellular functions
and structures, in addition to tissue damage, such as hemorrhage,
diffuse axonal damages, and contusions
TBI
• A pervasive and damaging form of acquired brain injury
• Acute, subacute, and chronic cell death processes
• Extended neuroinflammation can worsen secondary
degradation of brain function and structure
• Mesenchymal stem cell transplantation has surfaced as
a viable approach as a TBI therapeutic due to its
immunomodulatory and regenerative features
 TBI
Represents physical damage to the brain tissue
Induces transitory or permanent neurological disabilities

Activates an important inflammatory response

Lead to neuronal loss and further brain damage
Results in long-lasting patterns of neurological deficits
including motor, sensory, and cognitive abnormalities
Large anterior frontal
hemorrhagic contusions,
diffuse brain edema, herniation
 Regenerative Therapy TBI
• A very complex disease
• No effective treatments able to reduce
the effects of the primary injury
• Therapies capable of blocking their
progression
• In recent decades :
• NSCs and MSCs (BM-MSCs, AT-
MSCs and UC-MSCs) àreduce the
effects of post-traumatic brain
injury
• BM-MSCs administrated via
intravenous and via lumbar
puncture, shown improvement in
Schematic illustration of the neurovascular unit under normal damaged brain areas
physiological conditions and TBI pathological conditions
Medicina 2020, 56, 137
Zhou et al. Cell Communication and Signaling (2020) 18:62
 Stem Cell therapy is broadly applied to the cure of
the majority of diseases, particularly TBI
Mature Stem Cells have demonstrated prospective novel
situations for TBI Stem Cell therapy
Major Stem Cell Sources and
The Therapeutic Focus of Transplantation of Stem Cells

Neural Stem Cells (NSCs)

Bone marrow-derived Mesenchymal
Stem Cells (BMSCs)
Adipose-Derived Stem Cells
(ADSCs)
Embryonic Stem Cells (ESCs)
induced Pluripotent Stem Cells
(iPSCs)
 Studies Related to Stem Cell for TBI
human induced Pluripotent SCs
(hiPSCs) can decode the
molecular pathways of
degeneration and recovery of
neuronal and glial function
 induced Pluripotent Stem Cells (iPSCs)

Issues and solutions for achieving regenerative cell medicines derived from iPSCs
 Studies Related to Stem Cell for TBI

Schematic representation
summarizing the effect of
Pioglitazone (PG) and hMSC
combination treatment on improving
outcomes in rats after TBI

Scient Rep 2019, 9

 The potential mechanism of MSCs involved in anti-inflammatory and
immunomodulatory after TBI

Front in Cell Neurosci 2019

 Qin et al.
Stem Cell Research & Therapy 2022,
13:341

Proposed mechanism. FbMSC application reduces the activation of microglia cells and astrocytes and alleviates glutamate excitotoxicity.
Abbreviations: FGF1, acidic fibroblast growth factor1; FGFR, acidic fibroblast growth factor1 receptor; GLT-1, glutamate transporter-1; GLAST,
glutamate-aspartate transporter; iNOS, inducible nitric oxide synthase; IL6, interleukin 6; IL-10, interleukin-10
TBI Pathology & MSC-
related Treatment
Mechanisms

Oxid Med & Cell Long 2022

Acquired brain injury causes, pathophysiology,
and relation to primary and secondary cell death

Mesenchymal stem cell transplantation stands

as an attractive option for attenuating the
inflammation induced by stroke and TBI

CNS Neurosci Ther 2020;26:603–615

.
 Schematic diagram of TBI - associated secondary cell death and MSC therapy
Transplantation of MSCs may sequester the secondary cell death of TBI by reducing
neuroinflammation acutely,
subacutely, and chronically

Cell Transplant 30,

2021
Pathophysiological Heterogeneity Detected in TBI

Antioxidants 2020, 9, 297

 Zhou et al. Cell Comm & Signaling, 2020, 18:62

Potential therapeutic targets regarding astrocyte Schematic illustration of

derived molecules following TBI the glutamate-glutamine cycle in astrocytes
 Stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF)
treatments have shown neuroprotective and neurorestorative effects in the subacute
and chronic phases of experimental TBI
The SCF + G-CSF-enhanced myelin repair is positively correlated with the proliferation of oligodendrocyte
progenitor cells in the subventricular zone. These findings reveal the therapeutic potential of SCF + G-CSF in myelin
repair in the chronic phase of severe TBI and shed light on the mechanism underlying SCF + G-CSF- enhanced
remyelination in chronic TBI.

A schematic flowchart of the experiment

Cells 2023, 12, 705
Neurogenesis and Angiogenesis After TBI

BJA 2015, 115

Angiogenesis
Cell treatments have been shown as valuable equipment that
could reduce acts of TBI

PRISMA
flow chart of the study
A Clinical Trial to Determine the Safety and Efficacy of Hope Biosciences Autologous
Mesenchymal Stem Cell Therapy for
the Treatment of Traumatic Brain Injury and
Hypoxic-Ischemic Encephalopathy
Single arm, non-randomized study to determine safety and treatment effect of
three infusions of HB-adMSC (2 x 100 million total cells per dose) in adult patients
with sub-acute or chronic neurological injury
HB-adMSCs will be infused three times over a six week period, spaced 14 days apart

Hope Biosciences autologous adipose-derived mesenchymal stem cells

Actual Study Start Date : January 1, 2020
Estimated Primary December 31, 2024
Completion Date :
Estimated Study December 31, 2024
Completion Date :
 Stem Cell for TBI
Transplantation Methods
• A routine examination to exclude surgical contraindications and administration of
local anesthesia,
• A lumbar puncture was performed in the L3–4 or L4–5 intervertebral space,
• The puncture needle had been confirmed to penetrate into the subarachnoid space,
2 ml of stem cell suspension (containing 10 million stem cells) was slowly injected
into the subarachnoid space,
• This transplantation procedure was performed 4 times over an interval of 5–7 days
• After transplantation : patient body temperatures, heart rates, blood pressures,
oxygen saturations and respiratory rates were monitored for 6 h using a
multifunctional monitor
Brain research, 2013, 1532; 76–84 Confirmed the efficacy and safety of the treatment with UCMSCs in
patients with TBI sequelae
 SCI Spina Cord Injury

The mechanisms of Stem Cell therapy for SCI The application process of stem cells (SCs) for SCI
 Regenerative Therapy Gene Therapy

Spinal Cord Injury Pathology and Regenerative Therapeutics

F1000Research 2020, 9
 SCI

Cells 2023, 12, 120

 Neuroplasticity and regeneration
after spinal cord injury

Timeline of pathophysiological
changes following spinal cord injury

NASSJ 2023, 15
Kurru Sumange