Pivotal role of paracrine effects in stem cell therapies in regenerative medicine: can we translate stem cell-secreted paracrine factors and microvesicles into better therapeutic strategies?

Abstract

Although regenerative medicine is searching for pluripotent stem cells that could be employed for therapy, various types of more differentiated adult stem and progenitor cells are in meantime being employed in clinical trials to regenerate damaged organs (for example, heart, kidney or neural tissues). It is striking that, for a variety of these cells, the currently observed final outcomes of cellular therapies are often similar. This fact and the lack of convincing documentation for donor --recipient chimerism in treated tissues in most of the studies indicates that a mechanism other than transdifferentiation of cells infused systemically into peripheral blood or injected directly into damaged organs may have an important role. In this review, we will discuss the role of (i) growth factors, cytokines, chemokines and bioactive lipids and (ii) microvesicles (MVs) released from cells employed as cellular therapeutics in regenerative medicine. In particular, stem cells are a rich source of these soluble factors and MVs released from their surface may deliver RNA and microRNA into damaged organs. Based on these phenomena, we suggest that paracrine effects make major contributions in most of the currently reported positive results in clinical trials employing adult stem cells. We will also present possibilities for how these paracrine mechanisms could be exploited in regenerative medicine to achieve better therapeutic outcomes. This approach may yield critical improvements in current cell therapies before true pluripotent stem cells isolated in sufficient quantities from adult tissues and successfully expanded ex vivo will be employed in the clinic.

Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

“…However, as indicated by conditioned medium experiments in the present study, not only secreted factors but also target cell contact [8,31] or high EV concentration [21,32] are required to fully induce an immunomodulatory effect, at least in vitro. It has been established that after surface receptor interaction, internalisation or fusion to target cell membranes, EVs transfer proteins, lipids, functional mRNAs and miRNAs that control transcription, proliferation and immunoregulation [14,[32][33][34][35].…”

How stem cells speak with host immune cells in inflammatory brain diseases

“…This results in the formation of a gradient of the signaling molecule with proximal target cells responding differently according to the concentration they are exposed to. In regenerative medicine grafted stem cells secrete a variety of paracrine factors, including interleukins, colony-stimulating factors, prostaglandins, and growth factors, which regulate interactions with the environment (Ratajczak et al, 2012).…”

Cell therapy using retinal progenitor cells shows therapeutic effect in a chemically-induced rotenone mouse model of Leber hereditary optic neuropathy

“…This can be shown to be the case with photoreceptor transplants, 13 but may not be the case for other stem cells delivered to other sites in the body, with a paracrine mode of action favoured for some. [26][27][28] In this case, the premise is that secretion of hormones, growth factors and/or extracellular matrix components by the stem cells, in complex dialogue with pre-existing damaged tissue, may be stimulating transplanted cells to secrete therapeutic substances in response to the injured host tissue, thereby providing benefit. [26][27][28] The addition of pRPCs with glial potential to damaged retinas may enhance natural repair processes, by physical contact and structural repair, by providing an antiapoptotic effect (as suggested by increased Bcl2 levels), and by secretion of hormones and/or growth factors [26][27][28] or, perhaps, via increased glial protection of normally unmyelinated segments of ganglion cell axons.…”