Although the secretome of mesenchymal stem cells (MSCs) has a great potential to be used in CNS regenerative therapies, tissue derived MSCs are a limited source which often need to be surgically harvested and present intrinsic donor variability. Induced pluripotent stem cells (iPSCs) conversely, can be easily generated and highly expanded from accessible somatic cell sources and differentiated into mesenchymal stem cells (iMSCs), which have been described to present a rejuvenated phenotype. Here, we aim to compare the replicative senescence of bone marrow derived MSCs (BM-MSCs) and iMSCs under human platelet lysate (hPL) supplementation and address its impact on secretome composition. For that, we have compared the proliferation and replicative senescence of iMSCs and BM-MSCs on a long-term culture, by cumulative population doublings, expression of senescence associated β-Gal (SA-β-Gal), P16-INK4A, P53 and P21 gene expression and the increase in cell area (hallmarks of senescence). Finally, we compared BM-MSC and iMSC secretory profiles by a non-targeted mass spectrometry approach, evaluated the concentration of important neuroregulatory factors on the secretomes of early and late passage cells from both populations with a membrane-based antibody array, and assessed how the differences seen in these factors could affect their immunomodulatory capability with a mouse mixed glial culture. We show that iMSCs and BM-MSCs under hPL supplementation maintain their MSC properties and that iMSCs displayed higher proliferation, were capable of a higher total number of duplications and presented a decreased percentage of SA-β-Gal positive cells, decreased P16-INK4A and P21 gene expression and decreased increase in cell area compared with BM-MSCs. Furthermore, iMSCs and BM-MSCs presented a very similar secretory profile, with only 2 out of 136 proteins being significantly different in concentration in the proteomic analysis. Finally, the secretomes of both cells presented important neuroregulatory factors, with both having an upregulation of IL-6 and IL-8 at late passages which corroborated with a decreased immunomodulatory capability. In conclusion, we show that iMSCs can be expanded in hPL and that they have a similar secretory profile to BM-MSCs, but present decreased replicative senescence, therefore being a promising and more standardizable alternative to produce large quantities of secretome as needed for clinical purposes.