Mesenchymal stem cells (MSCs) have unique features such as self-renewal and ability to differentiate into multiple cell types both in vitro and in vivo into (1,2,3) which makes these cells attractive for therapeutic applications. MSCs and exosomes from MSCs produce many bioactive molecules The effects of these molecules have been overemphasized to possess immunomodulatory activity (3) to the extent that the regenerative action has been claimed to be manifest in-vivo without viable stem cells. Most of the paracrine concept is based on studies done in animal models and in-vitro studies that have shown to inhibit T cell activation, dendritic cell differentiation, B cell proliferation, and Immunosuppression (4,). The role of the Paracrine effect has changed the significance of stem cells as direct mediators of the observed regenerative effects. So much so, currently many companies are selling MSCs of cord blood origin and do not hesitate to claim that viability of MSCs have no significance and promote their products based on total cell counts without any viable MSCs, and 100 percent effective with claims to treat any disease via a drug-like action by paracrine factors.
The functional mechanism (s) in tissue regeneration and homeostasis is not clear and studies in animal models of disease have helped little, if any, to understand how these cells work in-vivo (5). In as much as such studies are essential to elucidate theoretical postulates, we are far away from a pragmatic rational as to how these cells manifest their therapeutics effects in-vivo and deny the direct role and viable stem cell need to treat disease.
Results of a clinical study (6),undeniably prove that stem cells work in-vivo through their stemness. A patient with acute myeloid leukemia has been cured of HIV infection following allogeneic hematopoietic stem cell transplants from a homozygous CCR5Δ32 donor.It is remarkable that in this patient, the viral load has been maintained at zero and the immune cell functionality has been normal for more than 12 years. If the grafted stem cells did not survive and maintained their ability to produce and replenish the CCR5 negative population of progenitors and or grafted stem cells, the period of protection from HIV would have been only for a few hours, or at best a few days, until the “Paracrine Effect” vanished with disappearance or clearance of the grafted cells in the patient’s system. Additional published data (7) clearly directs us to the value of stemness in regenerative medicine without undermining the importance and or contribution of factors generated by viable stem cells.
It will be important to show in-vivo the persistent survival and differentiation of the stem cells, if such a result can be accomplished. Current techniques to determine the fate of transplanted cells are highly invasive, requires multiple tissue biopsies, and limit our ability to monitor transplanted cells in real time. Until a reliable technique is developed, the only rational explaination for the clinical observation (7) is that patient’s immune system has successfully hosted the grafted CCR5 negative bone marrow cells, which have survived and have generated competent CCR5 negative progenitors to maintain normal immune system function and keep the virus under control.
1. Friedenstein, A. J., Chailakhyan, R. K., Latsinik, N. V., Panasyuk, A. F., and Keiliss-Borok, I. V. (1974). Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation 17, 331–340
2. Friedenstein AJ, Piatetzky S II, Petrakova KV. Osteogenesis in transplants of bone marrow cells. JEmbryolExpMorphol. 1966; 16:381–90
3. Pittenger MF, et al. Multilineage potential of adult human mesenchymal stem cells. Science.1999;284:143–7.
4. MeirellesLda S, Fontes AM, Covas DT, Caplan AI. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev. 2009; 20:419–27.
5. Ying Zhou et al 2013, Stem cell research and Therapy Stem Cell Research & Therapy 2013, 4:3 Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in …
6. Hütter G, et al. (2009) Long-term control of HIV by CCR5 Delta32/Delta32 stem-celltransplantation. N Engl J Med 360(7):692–698
7. Boregowda SV , Mesenchymal Stem Cells: The Moniker Fits the Science. - NCBI - 2017 Stem Cells. 2017 Sep 28.