Mesenchymal Stromal Cells to Treat Brain Injury (Bioengineering in Neurological Disorders) Part 2

Trophic support

Transplanted MSCs augment host repair and recovery primarily through direct and indirect trophic support. MSCs secrete a plethora of factors that are known to promote neural cell survival and regeneration through paracrine signaling to neural, vascular, and immune cells. An overview of relevant trophic factors found to be secreted by human bone marrow-derived MSCs in vitro is provided in Table 3. Which of these factors are secreted in the injured brain is under current investigation. Research is also ongoing to determine the exact or even the most critical mechanism(s) governing the beneficial effects of MSC transplantation. For now, we make a leap of knowledge based on existing evidence. There are numerous studies demonstrating that transplanted MSCs promote certain aspects of recovery (e.g., decrease apoptosis, increase neurogenesis, synaptogenesis, and angiogenesis) in the injured brain. Concurrently, there are other studies showing that factors known to be secreted by MSCs are involved in mechanisms that promote these same aspects of recovery.

Reference

Detection Method

Trophic Factors Found

Abbreviation

(Haynesworth et al., 1996)

ELISA of

Conditioned

Medium

Granulocyte colony stimulating factor


Granulocyte-macrophage colony stimulating factor Interleukin-11 Interleukin-6

Leukemia inhibitory factor Macrophage colony stimulating factor

Stem cell factor

G-CSF

GM-CSF

IL-11

IL-6

LIF

M-CSF SCF

(Potian et al., 2003)

Cytokine Array of

Conditioned

Medium

Angiogenin

Granulocyte colony stimulating factor

Granulocyte-macrophage colony

stimulating factor

Growth related oncogene-α

Interleukin-6

Interleukin-8

Monocyte chemoattractant

protein-1

Oncostatin M

Transforming growth factor-ß

Angiogenin G-CSF

GM-CSF

GROa

IL-6

IL-8

MCP-1

OSM TGFß

(Kinnaird et al., 2004)

ELISA or

Immunoblotting of

Conditioned

Medium

Angiopoietin-1 Fibroblast growth factor-2 Interleukin-6

Monocyte chemoattractant protein-1

Platelet derived growth factor Placental growth factor Vascular endothelial growth factor-A

ANG-1

FGF-2

IL-6

MCP-1

PDGF PlGF

VEGF-A

(Arnhold et al., 2006)

ELISA of

Conditioned

Medium

Brain derived neurotrophic factor Glial cell line-derived neurotrophic factor Nerve growth factor

BDNF GDNF NGF

(Crigler et al., 2006)

ELISA of

Conditioned

Medium

Brain derived neurotrophic factor Interleukin-11 Nerve growth factor Stromal derived factor-1

BDNF IL-11 NGF SDF-1

(Wang et al., 2006)

ELISA of

Conditioned

Medium

Hepatocyte growth factor Insulin-like growth factor-1 Vascular endothelial growth factor

HGF IGF-1 VEGF

Reference

Detection Method

Trophic Factors Found

Abbreviation

(Potapova et al., 2007)

ELISA of

Conditioned

Medium

Angiogenin

Angiogenin

Bone morphogenetic protein-2

BMP-2

Interleukin-6

IL-6

Interleukin-8

IL-8

Interleukin-11

IL-11

Monocyte chemoattractant protein-1

MCP-1

Vascular endothelial growth factor

VEGF

(Schinkothe et al., 2008)

Cytokine Array of

Conditioned

Medium

Cytokine Array of

Conditioned

Medium

Angiopoietin-2

ANG-2

Fibroblast growth factor-4

FGF-4

Fibroblast growth factor-9

FGF-9

Granulocyte colony stimulating factor

G-CSF

Growth related oncogene

GRO

Hepatocyte growth factor

HGF

Interleukin-8

IL-8

Interleukin-11

IL-11

Interleukin-17

IL-17

Monocyte chemoattractant protein-1

MCP-1

Neuro trophin-4 / 5

NT-4/5

Oncostatin M

OSM

Placental growth factor

PlGF

Tissue inhibitors of metalloproteinase-1

TIMP-1

Vascular endothelial growth factor

VEGF

Bone morphogenetic protein-4

BMP-4

(Tate et al., 2010)

Bone morphogenetic protein-7

BMP-7

Dickkopf-1

DKK-1

Fibroblast growth factor-7

FGF-7

Heparin-binding epidermal growth factor-like growth factor

HB-EGF

Hepatocyte growth factor

HGF

Interleukin-6

IL-6

Monocyte chemoattractant protein -1

MCP-1

Platelet derived growth factor-AA

PDGF-AA

Vascular endothelial growth factor

VEGF

Collagen I

Collagen I

(Lai et al., 2010)

Immunofluorescence of Extracellular Matrix

Decorin

Decorin

Fibronectin

Fibronectin

Laminin

Laminin

Perlecan

Perlecan

Table 3. Factors secreted in vitro by human bone marrow MSCs that may affect neural recovery.

The assumption is that some combination of these pro-recovery mechanisms occurs when MSCs are transplanted into the injured brain and that MSC-secreted factors are essential for these effects. Table 4 reviews potential beneficial mechanisms of action for repair and regeneration of the injured brain provided by MSC-secreted factors. The table provides references that demonstrate that the protein of interest enhances either 1) neuroprotection, 2) neural stem/progenitor cell proliferation or migration, 3) neural stem/ progenitor cell differentiation, 4) neuritogenesis or synaptogenesis, 5) angiogenesis, or 6) another mechanism involved in recovery (such as reducing inhibitory components of the glial scar). While these entries are based on a thorough search, it is not intended to be completely exhaustive. Also, only the beneficial aspects of the various growth factors are presented. Some factors that enhance one pathway act as inhibitors in another (e.g., the proinflammatory molecule interleukin-17 potentiates neuronal cell death but supports angiogenesis). Since these studies often examine pathways individually, it is not clear which are the primary mechanisms that occur when (if) the molecule is secreted by MSCs in the injured brain. Further, the exact timing and concentration of the trophic factor are likely critical in determining to which pathways they contribute.

tmpD-61

Promotes Neuroregeneration

tmpD-63

Additional

tmpD-64 tmpD-65 tmpD-66
tmpD-67

Angiogenin

(*Distler et al., 2003)

ANG-1

(*Hansen et al., 2008)

(*Ohab & Carmichael, 2008)

(*Hansen et al., 2008)

(*Distler et al., 2003)

Restore BBB (Nag et al., 2011)

ANG-2

(Liu et al, 2009)

neuronal (Liu et al, 2009)

in presence of

VEGF (*Distler et al., 2003)

BDNF

(*Lykissas et al, 2007)

(*Bath & Lee, 2010; *Schabitz et al, 2007)

neuronal (*Bath & Lee, 2010)

(Gascon et al., 2005; *Lipsky & Marini,

2007; *Lykissas et al., 2007)

(Qin et al., 2011)

BMP-2

(Iantosca et al., 1999)

astrocytic (*Sabo et al., 2009)

(Gratacos et al, 2001)

BMP-4

(Iantosca et al., 1999)

astrocytic (*Sabo et al., 2009)

BMP-7

(Yabe et al., 2002)

(Chou et al., 2006)

astrocytic (Gajavelli et al., 2004)

Promotes Neuroregeneration

tmpD-68 tmpD-69 tmpD-70 tmpD-71 tmpD-72

Additional

DKK-1

(Endo et al., 2008)

(Smadja et al., 2010)

FGF-2

(^Alzheimer & Werner, 2002; *Zechel et al., 2010)

(*Mudo et al., 2009; *Zechel et al, 2010)

(*Mudo et al., 2009; *Zechel et al, 2010)

(*Zechel et al., 2010)

(*Distler et al., 2003; Kumar et al, 1998)

tmpD-73

FGF-4

(Kosaka et al., 2006)

neuronal (Kosaka et al., 2006)

(*Fan & Yang, 2007)

FGF-7

(Sadohara et al, 2001)

(Terauchi et al., 2010)

(Gillis et al., 1999)

FGF-9

(Lum et al., 2009)

(Lum et al., 2009)

neuronal (Lum et al, 2009)

(Frontini et al., 2011)

G-CSF

(Schabitz et al., 2003; Schneider et al, 2005; Sehara et al., 2007; Solaroglu et al, 2006)

(Schneider et al, 2005; Shyu et al, 2004)

neuronal (Schneider et al, 2005)

(Minamino et

al, 2005; Sehara et al., 2007)

tMSC homing (Deng et al., 2011)

GM-CSF

(Huang et al., 2007)

(Bouhy et al., 2006)

(Buschmann et al, 2003)

GDNF

(Lu et al, 2005;

Shang et al., 2011; Shirakura et al, 2004)

(Dempsey et al, 2003)

(Shirakura et al., 2004)

GROa

oligodendrocyt ic (Robinson et al, 1998)

(Bechara et al., 2007)

HB-EGF

(Opanashuk et al, 1999)

(Jin et al, 2002)

neuronal (Jin et al, 2004) and glial (Korblum 1999)

HGF

(Honda et al., 1995; Shang et al, 2011)

(Shang et al., 2011)

neuronal and glial (Shang et al, 2011)

(Hamanoue et

al., 1996; Shang et al., 2011; Shimamura et al, 2006)

(*Distler et al., 2003; Shang et

al, 2011; Shimamura et al, 2006)

t MSC homing (Neuss et al., 2004; Ponte et al, 2007; Son et al., 2006); φ

glial scar (Shang et al., 2011; Shimamura et al, 2006)

Promotes Neuroregeneration

tmpD-74 tmpD-75 tmpD-76 tmpD-77 tmpD-78

Additional

IGF-1

(Wilkins et al., 2001; Yamada et al, 2001)

(Dempsey et al, 2003; Joseph D’Ercole & Ye, 2008)

neuronal and glial (*Joseph D’Ercole & Ye, 2008)

(*Joseph D’Ercole & Ye, 2008)

(*Distler et al., 2003; LopezLopez et al., 2004)

tMSC homing (Ponte et al., 2007)

IL-6

(Swartz et al., 2001)

neuronal (Oh et al, 2010) and astrocytic (Taga & Fukuda, 2005)

(Oh et al, 2010)

(*Fan & Yang, 2007)

IL-8

(Araujo & Cotman, 1993)

(*Fan & Yang, 2007)

tMSC homing (Wang et al., 2002)

IL-11

neuronal (Mehler et al., 1993)

IL-17

(Numasaki et al, 2003)

LIF

(Nobes & Tolkovsky, 1995)

(Bauer et al.,

2003; Shimazaki et al, 2001)

(Blesch et al., 1999)

l^cell homing (Sugiura et al., 2000)

MCP-1

(Widera et al., 2004; Yan et al, 2007)

tMSC homing (Wang et al., 2002)

M-CSF

(Vincent et al., 2002)

(Minamino et al, 2005)

NGF

(*Lykissas et al., 2007; Shirakura et al., 2004)

neuronal (Yung et al, 2010; Zhu et al., 2011)

(Gascon et al.,

2005; *Lykissas et al., 2007)

(*Lazarovici et al, 2006)

NT-4/5

(*Lykissas et al, 2007)

neuronal (Shen et al, 2010)

(*Lykissas et al., 2007)

OSM

(Weiss et al., 2006)

oligoendrocytic (Glezer & Rivest, 2010)

(Vasse et al., 1999)

PDGF

(Iihara et al., 1997; Vana et al, 2007)

(Forsberg-Nilsson et al., 1998)

neuronal (Johe et al., 1996)

(*Beck & Plate, 2009; *Fan & Yang, 2007)

tMSC homing (Ponte et al., 2007)

PlGF

(Du et al, 2010)

(*Beck & Plate, 2009)

Promotes Neuroregeneration

tmpD-79 tmpD-80 tmpD-81 tmpD-82 tmpD-83

Additional

tmpD-84

SCF

(Dhandapani et

al., 2005; Erlandsson et al. , 2004; Li et al, 2009)

(Bantubungi et

al, 2008; Erlandsson et al, 2004; Zhao et al, 2007)

(Sun et al., 2006)

tmpD-85

SDF-1

("Ohab & Carmichael, 2008; Thored et al, 2006)

tmpD-86

TGFß

("Buisson et al., 2003; Lu et al, 2005)

(Ma et al, 2008; Mathieu et al., 2010)

(Yi et al, 2010)

("Beck & Plate, 2009; "Fan & Yang, 2007)

TIMP-1

(Tan et al., 2003)

VEGF

(Jin et al, 2000; Sun et al, 2003)

(Sun et al., 2003; Wang et al, 2007a; Wang et al., 2007b)

(Erskine et al., 2011; Jin et al, 2006)

("Greenberg & Jin, 2005; "Shibuya, 2009)

Collagen I

(Ma et al, 2004)

neuronal (Ma et al, 2004)

("Sottile, 2004)

Decorin

(Davies et al., 2004)

tmpD-87

Fibro-nectin

(Sakai et al., 2001; Tate et al, 2007)

("Henderson &

Copp, 1997; Tate et al, 2004;

Testaz & Duband, 2001)

oligodendrocyt

ic (Hu et al., 2009)

(Einheber et

al, 1996; "Pires Neto et al, 1999)

("Sottile, 2004)

Laminin

(Hall et al., 2008)

(Hall et al., 2008; "Perris &

Perissinotto, 2000; Tate et al., 2004)

neuronal (Boote Jones & Mallapragada, 2007; Tate et al, 2004)

("Colognato

and Yurchenco, 2000; "Pires-Neto 1999)

("Sottile, 2004)

tmpD-88

Perlecan

("Bix & Iozzo, 2008; Lee et al, 2011)

("Bix & Iozzo, 2008; Lee et al., 2011)

Table 4. Evidence of MSC-secreted factors promoting neuroprotection or regeneration.

"Indicates review article; NSC=Neural stem/progenitor cell; Growth factor abbreviations are defined in Table 3

Neuroprotection

Following the initial insult, secondary injury mechanisms persist and cause cell death to surrounding tissue. While the initial ischemic or mechanical insult causes immediate necrotic death, secondary cell death primarily occurs through apoptosis. MSCs secrete multiple factors known to promote neural cell survival (see Table 4). Human MSCs have been shown to rescue neural cells following in vitro injury (e.g., oxygen glucose deprivation, glutamate toxicity) via secreted soluble factors (Tate et al., 2010; Zhong et al., 2003) and ECM proteins (Aizman et al., 2009). There are several reports of decreased apoptotic markers and enhanced preservation of neural cells in the injury penumbra when transplanting MSCs following experimental ischemic stroke (Li et al., 2010; Li et al., 2002; Xin et al., 2010) or TBI (Kim et al., 2010; Xiong et al., 2009). For example, delivering human MSCs intravenously 1 day following experimental cerebral ischemia in rats led to significant reduction in apoptotic cell death in the injury penumbra as well as functional behavioral recovery (Li et al., 2002). This study also found an increase in BDNF and NGF in the ipsilateral hemisphere of MSC-treated rats at 7 days post-stroke; however, they did not distinguish whether these trophic factors were produced by the donor or host cells. Li et al. (2010) show that transplanting human MSCs into the injury penumbra 1 week following experimental cerebral ischemia in monkeys decreased apoptotic cell death and the lesion volume. Human MSCs transplanted into the injury cavity 1 week following experimental TBI in rats lead to enhanced cell survival in the hippocampus and improved functional recovery, and this was further improved when the MSCs were delivered within a collagen I scaffold (Xiong et al., 2009). Kim et al. (2010) found that delivering human MSCs intravenously 1 day post-TBI in rats improved functional recovery and enhanced host cell survival by increasing pAkt and decreasing caspace-3 cleavage. Further, this group reports increases in BDNF, NGF, and NT-3 in the MSC-treated brains, though they did not distinguish between donor or host origin. Clearly, exogenous MSCs provide neuroprotection following brain injury and this is one probable mechanism of action for their benefit.

Neuroregeneration

After brain injury, the brain attempts to regenerate by resorting to a developmental-like state with increased neurogenesis, neurite outgrowth, synaptogenesis, re-myelination, re-formation of the blood brain barrier, and angiogenesis. Once thought to be unable to regenerate, it is now known that neural stem cells persist in the normal adult brain (neurogenic zones include the subventricular zone in the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus). After an ischemic or traumatic injury, endogenous neural stem cells proliferate, migrate to the site of injury, and differentiate into neurons and glia (Kernie & Parent, 2010). Neuroplasticity is the reorganization of neuronal circuitry by changing the number and/or strength of neurites and synapses. Such remapping occurs throughout life for learning and memory formation, and compensatory plasticity occurs in the spared tissue following brain injury (Nishibe et al., 2010). Neuroregeneration collectively includes neural stem/progenitor cell proliferation, migration and differentiation, neurite outgrowth, and synapse formation.

There are multiple in vitro studies showing that MSCs direct neuroregenerative processes. Bai et al. (2007) show that mouse neural stem cells had increased migration and neuronal and oligodendrocytic differentiation when they were cultured with either human MSCs or MSC-conditioned medium, indicating that soluble proteins are responsible for these effects. In related work, co-culture of human MSCs with rat neural stem cells revealed that MSCs promote differentiation into primarily astrocytes and oligodendrocytes (Robinson et al., 2011). However MSC-conditioned media promoted primarily oligodendrocytic differentiation (Robinson et al., 2011), indicating that matrix components or direct cell-cell contact also account for the effects of MSCs on neural stem cell differentiation. Indeed, Aizman et al. (2009) demonstrate that human MSC-derived ECM promotes differentiation of cortical cells into neurons, astrocytes and oligodendrocytes and also enhances neuronal neurite networks compared to single ECM proteins. Transplantation of MSCs augments endogenous regeneration following experimental ischemic stroke (Bao et al., 2011; Li et al., 2010; Li et al., 2002; Xin et al., 2010; Yoo et al., 2008) and TBI (Mahmood et al., 2004; Xiong et al., 2009). For example, both Bao et al. (2011) and Yoo et al. (2008) show that intracerebral transplantation of human MSCs 3 days following experimental cerebral ischemia in rats increases proliferation and migration of host neural stem cells and also decreases their apoptosis, thus enhancing neurogenesis. They also report enhanced behavioral recovery, and Bao et al. demonstrate increases in BDNF, NT-3, and VEGF in the brains of MSC-treated rats, though they do not identify the source of these cytokines. Xin et al. (2010) found that intravenous delivery of mouse MSCs 1 day following experimental stroke in mice lead to increases in axon fiber density, synaptogenesis and myelination. Following experimental TBI in rats, transplanted rat MSCs promoted increased proliferation and neuronal differentiation in neurogenic zones along with improved motor and sensory recovery (Mahmood et al., 2004). Xiong et al. (2009) also report that transplanting human MSCs intracerebrally 1 week post-TBI in rats leads to increased axonal fiber length and that the fiber length was directly proportional to performance on the behavior tasks. Multiple trophic factors secreted by MSCs may contribute to enhancing neuroregeneration (see Table 4).

The glial scar that forms following brain injury acutely acts to sequester the injury. Cellular components of the glial scar include reactive astrocytes, which help buffer excess glutamate and secrete neurotrophic factors, and activated microglia/ macrophages which clear out dead tissue and secrete neurotrophic factors. However, extracellular components of the glial scar that persists adjacent to the injury site have been found to inhibit neurite extension (e.g., neurocan, Nogo protein), thus limiting regeneration (for review, see Properzi et al., 2003). Transplantation of MSCs helps overcome this glial scar limitation following experimental stroke (Li et al., 2010; Li et al., 2005; Pavlichenko et al., 2008; Shen et al, 2008) and TBI (Zanier et al., 2011). Following ischemic stroke, rats treated with rat MSCs transplanted intravenously had decreased glial scar thickness at both the acute (3 and 6 days post-stroke; Pavlichenko et al., 2008) and chronic (4 months post-stroke; Li et al., 2005) phases. Along with decreased glial scar thickness, these studies report decreased lesion volume, enhanced regeneration, and functional recovery for animals treated with MSCs. Shen et al. (2008) show a decrease in neurocan (an inhibitory chondroitin sulphate proteoglycan) and enhanced axonal outgrowth in the injury penumbra when ischemic rats were treated with rat MSCs. Zanier et al. (2011) transplanted human umbilical cord blood-derived MSCs MSCs into the traumatically injured mouse brain and observed a decrease in reactive astrocytes in the glial scar region along with decreased lesion volume and functional recovery. Collectively, these data illustrate that exogenous MSCs promote neuroregeneration following brain injury by directly affecting neural stem/ progenitor cells and neurons and/or by reducing inhibitory glial scar components.

Angiogenesis

Another important aspect of regeneration is angiogenesis, which is the formation of new blood vessels from existing vasculature. In the adult, angiogenesis occurs after injury to help supply the damaged tissue with oxygen and nutrients. The process includes basement membrane disruption, endothelial cell migration and proliferation, three-dimensional tube formation, maturation, and stabilization by vascular smooth muscle cells. Each step is regulated by multiple cytokines and ECM molecules (for review, see Distler et al., 2003 or Fan & Yang 2007). Studies show that MSC-conditioned medium enhances endothelial cell proliferation (Kaigler et al., 2003) and promotes angiogenesis in vitro and in vivo (Kinnaird et al., 2004). Transplanting MSCs increases angiogenesis following experimental ischemic stroke (Omori et al., 2008; Onda et al., 2008; Pavlichenko et al., 2008) and TBI (Xiong et al., 2009). Potential pro-angiogenic factors secreted by MSCs are provided in Table 4. Notably, there is overlap between factors that promote angiogenesis and neurogenesis/neuritogenesis (reviewed in Emanueli et al., 2003 and Lazarovici et al., 2006). A unique feature of brain vasculature is the existence of the blood-brain barrier (BBB), formed by astrocyte end-feet surrounding specialized capillary endothelial cells in order to tightly regulate brain homeostasis. After injury, there is increased permeability of the BBB leading to edema (reviewed in Nag et al., 2011). Part of the repair process includes restoring the BBB, and regeneration includes formation of the BBB for new vasculature. Specific MSC-secreted factors such as ANG-1, FGF-2, and laminin may be involved in reforming the BBB following injury.

Immunomodulation

There is a potent immune response following ischemic and traumatic brain injury. The innate immune response is a part of the normal wound healing process; however, persistent inflammation can become cytotoxic. In addition to interacting with neural and vascular cells, MSCs communicate with immune cells and are now known to be immnosuppressive. Examining the interactions of MSCs with immune cells in vitro reveals that MSCs suppress T cell proliferation and activation, inhibit B cell proliferation and IgG production, prevent dendritic cell differentiation and migration, and shift the cytokine secretion profile of dendritic cells, helper T cells, and natural killer cells towards anti-inflammatory (reviewed in Mezey et al., 2010 and Nauta & Fibbe, 2007). Interestingly, studies that separate the MSCs from the immune cells using semi-permeable membranes indicate that soluble factors are critical for these effects. Candidate immunomodulatory factors secreted by MSCs include interleukin-6 (IL-6), transforming growth factor β (TGFß), prostaglandin E2, hepatocyte growth factor (HGF), indoleamine 2,3-dioxygenase (IDO), and monocyte colony stimulating factor (M-CSF) (reviewed in Mezey et al., 2010 and Nauta & Fibbe, 2007). Moreover, ECM proteins, such as fibronectin, also interact with immune cells (Mosesson, 1984; Nasu-Tada et al., 2005). Since shifting to a less inflammatory environment may facilitate neural repair and regeneration, immunomodulation is another feasible therapeutic mechanism of action for transplanted MSCs. Note that many immunomodulatory factors also have potential roles for directly promoting neural cell survival and regeneration (see Table 4). Likewise, NGF, the prototypic neurotrophic factor, has been shown to be anti-inflammatory (Villoslada & Genain, 2004). The interaction between angiogenesis and inflammation is also well-documented (for review, see Jackson et al., 1997 or Noonan et al., 2008), which further underscores the complexity and interrelatedness of these recovery mechanisms.

Challenges of identifying critical factors and mechanisms

Cell transplantation is a dynamic treatment that can target multiple therapeutic mechanisms. Advantages of transplanting cells compared to pharmaceutical treatments include the ability to 1) easily localize the treatment to the affected tissue, 2) supply a variety of trophic factors at physiologic concentrations, 3) persist long enough to alter the microenvironment of the injured brain tissue; and 4) interact with host cells. The beneficial effects of transplanted MSCs have been corraborated in vitro and in vivo and some potential pathways have been identified as described above. It is probable that a combination of multiple mechanisms of action synergistically contribute to improve functional recovery. While this ability to intervene along multiple pathways is desirable for a robust treatment, it makes identifying key mechanisms and factors challenging. Clarifying critical mechanisms of action would allow for treatments to be optimized to best facilitate these roles. Furthermore, difficulty pinpointing key mechanisms is a hurdle for developing potency assays for the clinical use of MSCs. Potency assays are critical for ranking and qualifying different cell lots on their ability to promote recovery. Another complication for determining potency of cells ex vivo is that transplanted cells interact with the host cells via paracrine signaling and possibly direct cell-cell contact. MSCs alter the secretion profile of host neural and immune cells, such as astrocytes and microglia (Gao et al., 2005; Xin et al., 2010), which further acts to promote repair and regeneration. Additionally, the secretion profile of MSCs is a function of the microenvironment and changes in the presence of injured brain tissue (Chen et al., 2002a, 2002b). Thus, there is a complex and dynamic web of players involved in MSC-mediated effects. Ideally, potency assays would be easily reproducible in vitro assays, however the interplay between donor cells and the host environment is difficult to model in vitro. Elucidating critical aspects of this therapy will be the focus of intense research for years to come.

Conclusion

Stroke and TBI are major contributors to death and persistent disability, and treatments that effectively promote repair and regeneration are desired. Cell transplantation is a promising treatment for brain injury, and MSCs are an attractive cell source due to their technical and safety advantages. Pre-clinical in vivo data show that transplanting MSCs enhances neuroprotection, promotes regeneration and/or suppresses inflammation. MSCs secrete numerous soluble and insoluble factors that are known to benefit the injured brain, which are likely crucial to the mechanisms of action governing MSC-mediated recovery. MSCs aid injured brain tissue by targeting multiple, non-mutually exclusive pathways, which is an advantage for a potential treatment, but a challenge for elucidating critical mechanisms and factors.

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