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This increased cellularity is thought to be a consequence of recruitment of cells to the viscera. We studied whether the local proliferation of splenic myeloid cells contributes to increased splenic cellularity. We found that a monocyte-like population of adherent splenic cells from <jats:italic>Leishmania donovani<\/jats:italic>-infected hamsters had enhanced replicative capacity <jats:italic>ex vivo<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> (BrdU incorporation, p&lt;0.0001). <jats:italic>In vitro<\/jats:italic> assays demonstrated that proliferation was more pronounced in the proinflammatory M1 environment and that intracellular infection prevented proliferation. Secondary analysis of the published splenic transcriptome in the hamster model of progressive VL revealed a gene expression signature that included division of tumoral cells (Z = 2.0), cell cycle progression (Z = 2.3), hematopoiesis (Z = 2.8), proliferation of stem cells (Z = 2.5) and overexpression of proto-oncogenes. Regulators of myeloid cell proliferation were predicted <jats:italic>in-silico<\/jats:italic> (CSF2, TLR4, IFNG, IL-6, IL-4, RTK signaling, and STAT3). The <jats:italic>in-silico<\/jats:italic> prediction was confirmed with chemical inhibitors of PI3K\/AKT, MAPK and STAT3 which decreased splenic myeloid cell division <jats:italic>ex vivo<\/jats:italic>. Hamsters infected with <jats:italic>L<\/jats:italic>. <jats:italic>donovani<\/jats:italic> treated with a STAT3 inhibitor had reduced <jats:italic>in situ<\/jats:italic> splenic myeloid proliferation (p = 0.03) and parasite burden. We conclude that monocyte-like myeloid cells have increased STAT3-dependent proliferation in the spleen of hamsters with visceral leishmaniasis and that inhibition of STAT3 reduces myeloid cell proliferation and parasite burden.<\/jats:p>","DOI":"10.1371\/journal.pone.0242337","type":"journal-article","created":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T18:49:39Z","timestamp":1605206979000},"page":"e0242337","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["In-situ proliferation contributes to the accumulation of myeloid cells in the spleen during progressive experimental visceral leishmaniasis"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8014-6330","authenticated-orcid":true,"given":"E. 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