Keywords
insomnia - mesenchymal stem cells - cell transplantation - interleukin-4
Introduction
Insomnia is a sleep disorder marked by trouble falling asleep, remaining asleep, or
combining both. Generally, it is diagnosed when people experience sleep difficulties
at least three nights a week and is considered chronic when it lasts for at least
three months.[1] Insomnia affects between 10% to 30% of the adult population, while the prevalence
can be higher in certain groups, especially for elderly people. Insomnia can lead
to various daytime impairments, such as tiredness, trouble focusing, mood swings,
and reduced productivity at work or school.[2] Mainly, two types of insomnia exist, namely primary insomnia and secondary insomnia.
The first one isn't linked directly to any other medical condition or issue. The second
one is caused by other underlying health problems such as stress, anxiety, depression,
medications, or medical conditions like asthma, chronic pain, or diabetes.[2]
[3] Despite its significant impacts on overall health outcomes, the etiology and pathophysiology
of insomnia are poorly understood. Sleep itself is mainly controlled by brain neural
circuits, including the suprachiasmatic nucleus of the hypothalamus.[4] In addition, recent studies indicate that peripheral tissues are also involved in
sleep regulation through sleep-immune crosstalk.[5] Treatments for insomnia are generally divided into non-medication treatments, including
cognitive behavioral therapy, and pharmacologic therapies, depending on its severity
and underlying causes. Pharmacologic treatments include benzodiazepine receptor agonists,
selective histamine H1 antagonists, melatonin receptor agonists, and orexin antagonists.
However, their adverse effects and some demerits have prohibited the wide and long-term
application of these treatments.[6]
Stem cell therapy, including bone marrow-derived mesenchymal stem cells (MSC), has
attracted significant attention for treating various diseases, including neurological,
cardiovascular, autoimmune, and metabolic diseases like diabetes. However, few studies
have been reported to indicate the therapeutic effects of the stem cell on insomnia.
MSCs are structured postnatal stem cells that can self-renew and maintain a wide range
of differentiation potentials, including those involved in sleep regulation.[7]
[8]
[9] MSCs also have immunomodulating roles by affecting several immune cells and their
secreted factors, including cytokines such as interleukin-4.[10]
[11]
[12] These immunomodulatory properties of MSCs would benefit several diseases related
to inflammation.[10] Thus, accumulated evidence suggests that MSCs could have therapeutic potential for
insomnia independent of disease comorbidities. Herein, I report on two patients whose
insomnia was successfully treated by intravenous administration of ex vivo-expanded MSCs.
Case Presentation
The first case was a 50-year-old man. Two years ago, he contracted COVID-19 and was
admitted to the ICU of another hospital, in which his cardiopulmonary function was
maintained by extracorporeal membrane oxygenation (ECMO) for two weeks. After the
incident, he developed insomnia. He took Quetiapine, Brotizolam, and Zolpidem to control
his insomnia. He had mild diabetes without any treatment history (HbA1c = 6.8%). The
second case was a 38-year-old man. He suffered from insomnia for more than 10 years.
He had atopic dermatitis, and borderline diabetes without any treatment history (HbA1c = 7.0%).
They were not taking any medications, including corticosteroids.
We performed MSC treatment by the methodology we previously described.[13] After thoroughly explaining the potential benefits and risks of the treatment, written
informed consent was obtained from the patients. Under local anesthesia, 60 ml of
bone marrow aspirate (BMA) was collected from the patient's ilium. The BMA was sent
to Kohjin Bio Ltd. (Saitama, Japan), a licensed laboratory for cell culture intended
for clinical use. Following good manufacturing practices, the laboratory purified
and expanded the MSCs over a month, limiting the number of passages to three. After
confirming cell viability and the expression of surface markers CD73, CD90, and CD105,
the cells were frozen and transported back to our clinic. The cells were thawed at
37°C and 1.5 × 108 cells were intravenously administered in 200 ml of saline. No adverse events were
observed during or after the treatment, and the patients remained stable until they
left the clinic.
Six months after the treatment, these patients came to the clinic for the follow-up.
While diabetic conditions were mildly attenuated (HbA1c: 6.0% for the first patient
and 6.3% for the second patient), the symptoms of insomnia were drastically improved
in both patients. The Athens Insomnia Scale (AIS), a reliable self-report questionnaire
consisting of eight items,[14] was improved from 16 (severe insomnia) to 0 (no insomnia) for the first patient
and from 14 (moderate insomnia) to 2 (no insomnia) for the second patient. Interestingly,
the plasma levels of interleukin-4, which were measured by CLEIA (chemiluminescent
enzyme immunoassay) at SRL, Inc. (Tokyo, Japan), were increased after the treatment
(230 pg/ml before the treatment vs. 390 pg/ml after the treatment for the first patient;
6.5 pg/ml before the treatment vs. 25.5 pg/ml after the treatment for the second patient).
They were highly satisfied with the treatment.
Discussion
Few studies are reporting the therapeutic effects of stem cells on insomnia. Indeed,
when we searched “insomnia and stem cell” in the PubMed database, there were no such
clinical reports except for ones that reported sleep problems in cancer patients received
with hematopoietic cell transplantation.[15]
[16] However, such problems appear to be caused by irradiation, rather than stem cell
transplantation itself.[17] As far as I know, there are no clinical studies reporting insomnia by stem cell
treatments without irradiation as a combination therapy. Thus, to the best of my knowledge,
this study, for the first time, showed the therapeutic effects of stem cells for insomnia.
We observed a drastic improvement in AIS score by the MSCs treatments in the current
two patients despite very mild improvements in diabetic conditions. The degree of
improvement of the AIS score (14 ± 2.8) should have a significant impact when considering
that even the new orexin receptor antagonist, Lemborexant, improved the AIS score
by less than 10 in the clinical trial.[18] Also, it is noteworthy that the current patients do not show any adverse events
generally associated with sleep medications, such as drowsiness, attention deficits,
and falls. While we did not measure other objective psychological or physiological
scores, AIS has been shown to be associated with daytime drowsiness, depressive symptoms,
and a decline in overall quality of life.[14] Most importantly, the current patients were well satisfied with the effects of MSC
treatments.
While we observed that plasma levels of IL-4 were increased after the MSC treatment,
IL-4 is often considered to be an anti-inflammatory and beneficial cytokine.[19] Moreover, several studies have shown that inflammation or inflammatory cytokines,
such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6)
could play a significant role in causing insomnia.[20] Also, people with chronic inflammatory conditions, such as rheumatoid arthritis,
inflammatory bowel disease, and chronic obstructive pulmonary disease (COPD), often
experience higher rates of insomnia.[2]
[3]
[5] Notably, MSCs have immunomodulating properties that would benefit several inflammation-related
diseases.[10] The immunomodulating effect of MSCs is reflected in T-cell properties, in which
they cause T(H)1 cells to decrease interferon-gamma (IFN-gamma) while affecting the
T(H)2 cells to increase secretion of IL-4.[11] Interestingly, one cellular study indicated that the anti-inflammatory effects of
MSCs were mediated through the stimulation of IL-4.[12] Moreover, several studies indicate that IL-4 could enhance the function of MSCs
in cellular differentiation, regeneration, and tissue remodeling.[21]
[22]
[23] While the exact role of IL-4 in insomnia is indeed unknown, if inflammation is mainly
involved in causing insomnia in the current patients, an increase in IL-4 levels might
contribute to the therapeutic effects of MSCs. Further studies analyzing other anti-inflammatory
or proinflammatory biomarkers would provide additional insights into the mechanism
of how MSC transplantation improved insomnia in the current cases.
Several studies indicate that sleep deprivation can negatively impact stem cell function,
potentially impairing their ability to repair and regenerate tissues.[24] Additionally, there's accumulated evidence that stem cells play an important role
in regulating sleep. Certain types of stem cells in the brain, such as neural stem
cells, may influence sleep patterns and circadian rhythms.[9] Of note, MSCs not only can differentiate such neural stem cells but also can support
their function through immunomodulation of cellular environments as well as via the
release of trophic factors.[7]
[8] These results indicate that sleep disorders and loss of stem cell function influence
each other, likely forming a vicious cycle, in which transplantation of ex-vivo expanded
MSCs might be an ideal therapeutic strategy for breaking such a vicious cycle.
There are some limitations in this study. First, we could not rule out that the drastic
improvements from insomnia were mediated by the attenuation of the diabetic condition,
although the changes in the diabetic marker HbA1c were very mild. Diabetes itself
is tightly linked to proinflammatory status, which is a promising target for MSCs,
and an increase of IL-4 might also be beneficial for diabetes through anti-inflammatory
properties.[10]
[25]
[26] Thus, it might be difficult to clearly distinguish the effects of MSCs on insomnia
independently of diabetes. Second, the etiology of insomnia in these cases was not
diagnosed. While around 85% of insomnia is caused by other underlying health issues,
known as secondary insomnia,[2]
[3] the possibility of primary insomnia could not be ruled out for the current cases.
Depending on etiology, the roles of inflammation or cytokines in insomnia should be
different. Thus, more thorough examinations before and after the treatment would be
necessary to understand the therapeutic effects of MSCs on insomnia.
Conclusion
In this case report, we observed two patients whose insomnia was drastically improved
following intravenous administration of MSCs. To our knowledge, this is the first
study documenting the therapeutic effects of MSCs on insomnia. Anti-inflammatory effects
through stimulating IL-4 might be a key to understanding the therapeutic effects of
MSCs on insomnia.
