Hematopoietic stem and progenitor cells improve survival from sepsis by boosting immunomodulatory cells
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Curated by eLife
Evaluation Summary:
This preclinical study reports on a novel strategy for sepsis. Sepsis induced by Group A Streptococcus (GAS) in mice leads to depletion of bone marrow HSPCs and mortality and infusion of naive donor HSPCs lower mortality but has no effect on bacterial burden. This supports that HSPCs infusion might attenuate the detrimental immune response in sepsis warranting further investigation of this novel concept.
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- Immunology and Inflammation (eLife)
Abstract
New therapeutic strategies to reduce sepsis-related mortality are urgently needed, as sepsis accounts for one in five deaths worldwide. Since hematopoietic stem and progenitor cells (HSPCs) are responsible for producing blood and immune cells, including in response to immunological stress, we explored their potential for treating sepsis. In a mouse model of Group A Streptococcus (GAS)-induced sepsis, severe immunological stress was associated with significant depletion of bone marrow HSPCs and mortality within approximately 5–7 days. We hypothesized that the inflammatory environment of GAS infection drives rapid HSPC differentiation and depletion that can be rescued by infusion of donor HSPCs. Indeed, infusion of 10,000 naïve HSPCs into GAS-infected mice resulted in rapid myelopoiesis and a 50–60% increase in overall survival. Surprisingly, mice receiving donor HSPCs displayed a similar pathogen load compared to untreated mice. Flow cytometric analysis revealed a significantly increased number of myeloid-derived suppressor cells in HSPC-infused mice, which correlated with reduced inflammatory cytokine levels and restored HSPC levels. These findings suggest that HSPCs play an essential immunomodulatory role that may translate into new therapeutic strategies for sepsis.
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Public Review:
With interest, I reviewed the manuscript by Morales-Mantilla et al., who report on a novel therapy, namely hematopoietic stem and progenitor cells (HSPCs) for sepsis. They describe that sepsis induced by Group A Streptococcus (GAS) leads to depletion of bone marrow HSPCs and mortality, and therefore attempt to improve outcome using infusion of naive donor HSPCs, which is successful, as it lower mortality. This effect appears not to be mediated by reducing bacterial burden, which is not affected by HSPC infusion, but rather by attenuation of the immune response, reflected by decreased levels of inflammatory mediators and increased abundance of myeloid-derived suppressor cells.
Strengths:
- The manuscript is well written and easy to follow.
- The paper includes interesting novel immunological data on the bone marrow response to …
Public Review:
With interest, I reviewed the manuscript by Morales-Mantilla et al., who report on a novel therapy, namely hematopoietic stem and progenitor cells (HSPCs) for sepsis. They describe that sepsis induced by Group A Streptococcus (GAS) leads to depletion of bone marrow HSPCs and mortality, and therefore attempt to improve outcome using infusion of naive donor HSPCs, which is successful, as it lower mortality. This effect appears not to be mediated by reducing bacterial burden, which is not affected by HSPC infusion, but rather by attenuation of the immune response, reflected by decreased levels of inflammatory mediators and increased abundance of myeloid-derived suppressor cells.
Strengths:
- The manuscript is well written and easy to follow.
- The paper includes interesting novel immunological data on the bone marrow response to severe infection.
- MDSC infusion is an interesting new therapy for sepsis and is shown to be effective in mice infected with GAS.
Weaknesses:
- In the reinfection model (influenza+GAS), it would have been much more interesting to infuse HSPCs in between infections to evaluate whether this therapy decreases vulnerability towards a secondary infection. The authors state in the discussion: "Interestingly, increased MDSCs during sepsis have also been associated with increased development of nosocomial infections (56)." This could still be the case with the therapy studied in the present paper, it was just not assessed in the proper way.
- The data presented in figure 7 is of little value, as (if I understand correctly) these were obtained in non-inflamed/infected mice. Therefore, conclusions such as "Whereas MDSCs did arise directly from infused cells, their numbers were not sufficient to account for the large increase in MDSCs observed in the HSPC-rescued mice. These data suggest that HSPC infusion contributes to MDSC expansion via both direct and indirect mechanisms." are not justified.
- I feel the authors are a bit too optimistic in stating "Our findings could lead to the development of an efficacious new therapeutic approach that could succeed where granulocyte infusions have fallen short". There are so many steps and hurdles that need to be taken before this kind of intervention could be translated to the clinic.
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Evaluation Summary:
This preclinical study reports on a novel strategy for sepsis. Sepsis induced by Group A Streptococcus (GAS) in mice leads to depletion of bone marrow HSPCs and mortality and infusion of naive donor HSPCs lower mortality but has no effect on bacterial burden. This supports that HSPCs infusion might attenuate the detrimental immune response in sepsis warranting further investigation of this novel concept.
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