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Xenogeneic cell\u2010based treatment with expanded human placenta stromal cells, predominantly from fetal origin (PLX\u2010RAD cells), were shown to mitigate significantly acute radiation syndrome (ARS) following high dose irradiation in mice, with expedited regain of weight loss and haematopoietic function. The current mechanistic study explores the indirect effect of the secretome of PLX\u2010RAD cells in the rescue of the irradiated mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The mitigation of the ARS was investigated following two intramuscularly (IM) injected 2 \u00d7 10<jats:sup>6<\/jats:sup> PLX\u2010RAD cells, 1 and 5 days following 7.7 Gy irradiation. The mice survival rate and their blood or bone marrow (BM) cell counts were followed up and correlated with multiplex immunoassay of a panel of related human proteins of PLX\u2010RAD derived secretome, as well as endogenous secretion of related mouse proteins. PLX\u2010RAD secretome was also tested in vitro for its effect on the induction of the migration of BM progenitors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A 7.7 Gy whole body mice irradiation resulted in ~25% survival by 21 days. Treatment with two IM injections of 2 \u00d7 10<jats:sup>6<\/jats:sup> PLX\u2010RAD cells on days 1 and 5 after irradiation mitigated highly significantly the subsequent lethal ARS, with survival rate increase to nearly 100% and fast regain of the initial weight loss (P &lt; 0,0001). This was associated with a significant faster haematopoiesis recovery from day 9 onwards (P &lt; 0.01). Nine out of the 65 human proteins tested were highly significantly elevated in the mouse circulation, peaking on days 6\u20139 after irradiation, relative to negligible levels in non\u2010irradiated PLX\u2010RAD injected mice (P &lt; 0.01). The highly elevated proteins included human G\u2010CSF, GRO, MCP\u20101, IL\u20106 and lL\u20108, reaching &gt;500 pg\/mL, while MCP\u20103, ENA, Eotaxin and fractalkine levels ranged between ~60\u2013160pg\/mL. The detected radiation\u2010induced PLX\u2010RAD secretome correlated well with the timing of the fast haematopoiesis regeneration. The radiation\u2010induced PLX\u2010RAD secretome seemed to reinforce the delayed high levels secretion of related mouse endogenous cytokines, including GCSF, KC, MCP\u20101 and IL\u20106. Additional supportive <jats:italic>in vitro<\/jats:italic> studies also confirmed the ability of cultured PLX\u2010RAD secretome to induce accelerated migration of BM progenitors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>A well\u2010regulated and orchestrated secretion of major pro\u2010regenerative BM supporting secretome in high dose irradiated mice, treated with xenogeneic IM injected PLX\u2010RAD cells, can explain the observed mitigation of ARS. This seemed to coincide with faster haematopoiesis regeneration, regain of severe weight loss and the increased survival rate. The ARS\u2010related stress signals activating the IM injected PLX\u2010RAD cells for the remote secretion of the relevant human proteins deserve further investigation.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12342","type":"journal-article","created":{"date-parts":[[2018,10,18]],"date-time":"2018-10-18T09:01:49Z","timestamp":1539853309000},"page":"1079-1092","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Rescue from lethal acute radiation syndrome (ARS) with severe weight loss by secretome of intramuscularly injected human placental stromal cells"],"prefix":"10.1002","volume":"9","author":[{"given":"Lena","family":"Pinzur","sequence":"first","affiliation":[{"name":"Pluristem LTD  Haifa Israel"},{"name":"Berlin\u2010Brandenburg Center for Regenerative Therapies (BCRT) and Institute of Medical Immunology and Department of Nephrology and Intensive Care Charit\u00e9\u2014University Medicine Berlin  Berlin 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