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PLoS One. 2020 Jan 23;15(1):e0227817. doi: 10.1371/journal.pone.0227817. eCollection 2020.

Tissue-resident macrophages can be generated de novo in adult human skin from resident progenitor cells during substance P-mediated neurogenic inflammation ex vivo.

Author information

Monasterium Laboratory GmbH, Münster, Germany.
Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Centre for Dermatology Research and NIHR Manchester Biomedical Research Centre University of Manchester, Manchester, United Kingdom.
Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
Division of Cell Matrix Biology and Regenerative Medicine, University of Manchester, Manchester, United Kingdom.


Besides monocyte (MO)-derived macrophages (MACs), self-renewing tissue-resident macrophages (trMACs) maintain the intracutaneous MAC pool in murine skin. Here, we have asked whether the same phenomenon occurs in human skin using organ-cultured, full-thickness skin detached from blood circulation and bone marrow. Skin stimulation ex vivo with the neuropeptide substance P (SP), mimicking neurogenic skin inflammation, significantly increased the number of CD68+MACs in the papillary dermis without altering intracutaneous MAC proliferation or apoptosis. Since intraluminal CD14+MOs were undetectable in the non-perfused dermal vasculature, new MACs must have differentiated from resident intracutaneous progenitor cells in human skin. Interestingly, CD68+MACs were often seen in direct cell-cell-contact with cells expressing both, the hematopoietic stem cell marker CD34 and SP receptor (neurokinin-1 receptor [NK1R]). These cell-cell contacts and CD34+cell proliferation were up-regulated in SP-treated skin samples. Collectively, our study provides the first evidence that resident MAC progenitors, from which mature MACs can rapidly differentiate within the tissue, do exist in normal adult human skin. That these NK1R+trMAC-progenitor cells quickly respond to a key stress-associated neuroinflammatory stimulus suggests that this may satisfy increased local MAC demand under conditions of wounding/stress.

Conflict of interest statement

The authors have read the journal's policy and the authors of this manuscript have the following competing interest: MB and JC are or were employed of Monasterium Laboratory GmbH. JG is a paid employee of Monasterium Laboratory GmbH, Münster. RP is the founder and CEO of Monasterium laboratory. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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