What factors determine the treatment effect of MSC (Part Two)

Posted by beauty33 on January 6th, 2020

2. Injection route

There are many reports of such clinical applications. We mainly focuses on the human and animal data of clinical research.

A. Intravenous injection (systemically)

Intravenous injection is the most commonly used and easiest route and allows the infusion of large numbers of MSCs.

The biggest drawback of intravenous injection is that the lungs can clear more than 60% of MSCs, resulting in a decrease in the number of MSCs that are chemotactic to the site of the injury.

Human umbilical cord blood-derived MSCs pass through the lungs more easily than human bone marrow MSCs, and the older donors are, the easier it is for bone marrow MSCs to be retained in mouse lungs; the number of MSC cells retained in the lungs are closely related with MSC cell surface expression α4 and α6. The higher the expression level, the less likely it is to be retained in mouse lungs. However, if MSCs are administered to patients in combination with integrin antibodies, the risks associated with intravenous injection of integrin antibodies need to be assessed.

In two small human clinical studies, peripherally infused MSCs were infused into patients using indium-labeled MSCs. Although most signals were found early in the lungs, most of the signals were transferred to the spleen and liver after 48 hours. Ten days after the MSCs were intravenously injected into the body, at least about 50% of the MSCs remained in the body to function, while the lungs had less than 5% retention.

Therefore, we cannot rely on animal research alone, and we need to combine clinical research to optimize the optimal treatment of MSC.

Interestingly, after intravenous injection of MSC in rats, the test was performed 96 hours later. Hypoxic environment increased the retention of MSC in the lungs and reduced the number of MSCs in the liver, spleen and kidneys.

From this perspective, when patients use MSC, it is best to increase the partial pressure of oxygen in the lungs, at least in a normal oxygen content environment.

B. Local intervention injection

Local interventional injections, including the use of combined biomaterials (such as bone scaffolds for orthopedic disorders), intrathecal injections for neurological diseases, and intratracheal injections for respiratory diseases, all help MSCs avoid the clearing of lungs.

(1) Intrathecal injection of spinal cord

Another common input route for MSC is intrathecal injection into the spinal cord.

Spinal cord intrathecal injection of MSC is commonly used to treat neuropathy diseases, including stroke, cerebral palsy, autism, etc., and this technique can also be applied to most children (including premature infants).

According to reports, umbilical cord-derived MSCs were injected intrathecally into 8 pairs of twin children with cerebral palsy. All patients received 4 intrathecal injections at intervals of 3-5 days, each (1.0-1.5) × 10 * 7 MSCs. After 6 months of treatment, motor function improved significantly. Another clinical study showed that intravenous and / or intrathecal injection of allogeneic MSCs can improve muscle tone, strength, language, memory, and cognitive ability in children with cerebral palsy.

Intrathecal injection of MSC under general anesthesia will cause adverse reactions related to infusion. Fever and vomiting are the most common and even severe seizures will occur; however, all symptoms will resolve spontaneously within 72 hours and during the follow-up period of 6 months, no further complications occurred. It is speculated that fever and vomiting may be related to general anesthesia.

(2) Microinjection into the brain parenchyma

In the clinical study of MSC in the treatment of cerebral palsy, the researchers evaluated the feasibility and effectiveness of intrathecal injection combined with cerebral parenchyma microinjection of MSC for cerebral palsy. In this clinical study, autologous bone marrow MSCs were cultured in vitro to 4-5 generations, using 2X107 MSC doses per injection; all patients received intrathecal MSCs, but patients with older or larger skulls (5 years old or head over 50 cm or larger), received 2 intrathecal injections before stereotactic surgery and received MSC microinjection in the parenchyma of the brain; the total motor function scores of all patients were improved to varying degrees, but the injection did not bring additional benefits. The researchers only observed transient hypothermia and wound pain, but no more serious adverse events.

A clinical study of local injection of bone marrow MSCs around the ischemic area of ​​the brain for stroke (onset more than 6 months) in 18 patients. All patients did not conduct rehabilitation therapy. After 1 year of observation and evaluation (ESS, NIHSS, mRS, and FM Total score and motor function score), various scores were improved; however, all patients experienced varying degrees of side effects due to local injections (analyzed independently of MSC), including headache, nausea, vomiting, depression, increased muscle tone , fatigue, elevated blood sugar, and elevated C-reactive protein.

(3) Intratracheal injection

Preterm infants are often accompanied by the risk of bronchopulmonary dysplasia (BPD). A small-scale clinical trial validates the feasibility of MSC intervention for BPD in preterm infants. The average weight of these 9 preterm infants with an average of 25.3 weeks of pregnancy was 793 grams; the MSC dose of the first 3 BPD children was 1X10 * 7 / kg, and the MSC dose of the last 6 BPD children was 2X10 * 7 / kg; after 7 days of treatment, the concentration of inflammatory factors in the bronchial secretion decreased significantly, and the Respiratory Severity Score improved significantly.

(4) Combined with biological scaffold

Stem cells combined with biological scaffolds are a new treatment for refractory diseases, especially neurological diseases.

It is reported that the use of autologous bone marrow MSC combined with demineralized bone matrix scaffold can achieve about 50% bone defect filling after 3 months, which is not suitable for general clinical application. In addition, some studies have shown that 79.1% filling is achieved without a bone scaffold, but the MSCs used have undergone osteogenic induction in vitro, indicating that cells are more important than their supporting structures. The use of donor bone as a growth stimulator may help MSCs for skull reconstruction.

MSC combined with biological scaffolds is a good application direction, and needs better research progress!

To be continue in Part Three…