Transplantation of Mesenchymal Stem Cells in Critically Ill Patients

Before COVID-19

1. Mesenchymal stem cells (MSCs) are multipotent, self-renewing stromal cells present mainly in the bone marrow and adipose tissue, that are able to differentiate into various cell types, including myocytes, adipocytes, osteoblasts and chondrocytes.²
2. MSCs have shown their effectiveness in immune-mediated inflammatory diseases²:
   • They have been recognized to have immunomodulatory, immunosuppressive, and regenerative effects, particularly through the secretion of paracrine factors.²
   • MSCs can lower pro-inflammatory cytokine secretion and stimulate anti-inflammatory cytokine production, therefore decreasing the severity of the immune system’s response to inflammation.²

Since COVID-19 Outbreak

1. Studies have demonstrated that the SARS-CoV-2 spike protein specifically recognizes the angiotensin I converting enzyme 2 (ACE2) receptor, so that ACE2 positive cells are infected by the virus.¹ In addition, the SARS-CoV-2 virus uses the serine protease TMPRSS2 for its spike protein priming.¹
2. The ACE2 receptor can be found on the alveolar type II cells in the lungs, which highly express TMPRSS2¹, as well as in the heart, liver, kidney and digestive organs’ cells.
3. Immune cells, such as macrophages and T and B lymphocytes, are negative for ACE2 receptors¹, suggesting that immunomodulatory therapies could be efficient in treating COVID-19 infection and/or complications.
4. A cytokine storm has been associated with poor outcomes and complications in infected patients, so preventing or attenuating it with immunomodulators could be beneficial.¹
5. A small study conducted with 7 patients who had COVID-19 induced pneumonia and who received intravenous MSC transplantation showed that¹:
   • MSCs are immune to COVID-19, being ACE2 negative and TMPRSS2 negative
   • Cytokine-secreting immune cells CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells were gone in 3 to 6 days
   • Levels of pro-inflammatory (TNF-α) and anti-inflammatory cytokines (IL-10, VEGF) were significantly better after treatment.
     
   • The seven patients in the MSC group had a better pulmonary function within 2 days after MSC transplantation, while three of them, including one critically ill were discharged within 10 days after treatment
   • No adverse effects were observed

This data comes from the analysis of a study enrolling 7 patients with COVID-19 induced pneumonia compared to 3 patients in a placebo group, conducted in Beijing YouAn Hospital in China, from January 23, 2020 to February 16, 2020. Diagnosis of coronavirus was confirmed using RT-PCR testing. Clinical outcomes were determined and analyzed during the 14 days after the intravenous injection of mesenchymal stem cells. Patients who had cancer or who had participated in another study in the last 3 months were excluded. Primary efficacy outcomes observed were the cytokines variation, the level of C-reactive protein in plasma and oxygen saturation.

Clinical trials for Mesenchymal Stem Cells are currently underway

Further studies should be done focused more on clinical outcomes, with larger cohorts of patients.

Sources:

1. Leng Z., Zhu R., Hou W., et al (March 9, 2020). Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia. Aging and Disease. https://doi.org/10.14336/AD.2020.0228
2. Saeedi, P., Halabian, R., & Imani Fooladi, A. A. (Septembre 25, 2019). A revealing review of mesenchymal stem cells therapy, clinical perspectives and Modification strategies. Stem cell investigation. https://doi.org/10.21037/sci.2019.08.11