lisato piastrinico ricco di PDGF dimostrato che spinge mesengenesi (lavoro GF)
 
cappello ispirato a discussione dei monospeophills in SCID
    Bone is a tissues highly re-modeled during the entire life and preserving a consistent capacity of healing an regeneration in response to injuries also in the adulthood. Both re-modeling \cite{Raggatt_2010} and regeneration \cite{Kalfas2001,Oryan2015} processes are orchestrated within specialized anatomical structures involving complex interactions between cells, soluble factors and extracellular matrix. The cell compartment involved in mantaining or restoring bone homeostasis is divide in "calciyfing/bone forming" or "bone resorbing" cells. Mesenchyme-derived cells as MSCs, chondroblasts, osteoblasts and osteocytes partecipate to the calcification process, while hemopoietic-derived osteoclasts are commonly exclusively associated to bone resorption. However, increasing amount of evidences points to the mesengenic potential of BM-derived hemopoietic cells, which could a have a role also in the new bone formation. Moreover, in response to injuries, not only resident bone and bone marrow cells has been indicated being involved in regeneration but also circulating cells has been hypothesized able to engraft and partecipate to the calcification process. In particular, there are neglected evidences that circulating monocytes, conventionally believed to only differentiate into Mϕ and DCs, can differentiate into a variety of non-phagocytic cells (REF). 
Mesengenic potential of the circulating monocytic compartment
Monocyte-derived Multipotential cells (MOMCs)
     In 2003, Kuwana M. et al. reported the isolation of a primitive cell population named monocyte-derived multipotential cells (MOMCs), from circulating CD14-positive cells in humans. MOMCs has been characterized, in culture, by the expression of CD14, CD68, CD45 and CD34 but also type I/III collagen, showing a fibroblast-like morphology and mesenchymal differentiation capability \cite{Kuwana2003}. MOMCs are isolated from peripheral blood mononuclear cells (PB-MNCs) cultured in DMEM/10% FBS on fibronectin-coated plastics, and their origins from circulating CD14-positive cells has been confirmed by fluorescent cell tracking and cell depletion. Interestingly, MOMCs retain the ability to differentiate into phagocytes and later on, it has also been reported a consistent angiogenic potential both in vitro and in vivo \cite{Kuwana2006}. MOMCs share several peculiar features with MPCs, as Ac-LDL uptake, the retention of the mesengenic/angiogenic potential and very similar phenotype characterized by weak expression of CD14, CD45, CD13 and CD105 and consistent expression of CD31, CD11b, CD11c and HLA-I/II.  Their morphology looks very similar in light and electronic microscopy and both these cell population express pluripotency-associated genes as OCT-4 and NANOG \cite{Seta_2010}. However, differences between MOMCs and MPCs are evident. Firstly these two cell populations are generated from different ex vivo progenitors; circulating CD14-positive cells for MOMCs and BM-derived CD14-negative cells for MPCs. Secondary, MPCs are CD34-negative and require human serum supplementation conversely CD34-positive MOMCs are cultured with FBS but on fibronectin coated plastics. The ex vivo progenitors of of MOMCs have not been fully identified as different circulating precursors could be included in the CD14-positive fraction, however an alternative mechanism leading to these cells, could be hypothesized. In fact, Authors did not exclude that different and specific culture conditions could drive circulating monocytes toward a "de-differentiation" pathway, acquiring a more immature phenotype and differentiation properties.  
Programmable Cells of Monocytic Origin (PCMO)
    The idea that peripheral blood monocytes could acquire a plasticity following an in vitro de-differentiation has been successively supported by the report of programmable cells of monocytic origin (PCMO). These cells are obtained from circulating monocytes isolated by plastic adherence from peripheral mononuclear cells in RPMI-1640 supplemented with 10% of human type AB serum. The subsequent treatment with low doses of M-CSF and IL-3 for six days led to proliferating PCMO capable of differentiation into neohepatocytes and pancreatic islet-like cells \cite{Ruhnke_2005}. Moreover, PCMO express some endothelial features \cite{Hutchinson2007} and recent data suggest that these cells are also able to differentiate in vitro toward osteoblast-like cells \cite{A_il_2017} and collagen type-II producing chondorcytes \cite{Pufe2008}. Interestingly, similar to MPCs and MOMCs, PCMO express OCT-4 and NANOG but the de-differentiation process has been analyzed in more details at the molecular levels. Ungefroren et al. demonstrated that the reactivation of OCT-4 and NANOG genes in peripheral monocytes is essential to generate PCMO, also combined with the expression of other reprogramming factors as KLF4 and MYC, but not SOX2 \cite{Ungefroren_2010}, this molecular signature is identical to what reported in MPCs (Pacini 2010). Moreover, Authors also showed that after "reprogramming" in PCMO inducing medium the percentage of CD14-positive cells vary from 90-95% to around 45%, ranging from 30% to 60%, while other markers as CD86 and  HLA-DR remained constant over the culture time suggesting the emergence of CD14negCD86+HLA-DR+ sub-population matching precisely the MPC phenotype. These data strongly suggest that the induction of PCMO from circulating monocytes, is exerted by the acquisition of the MPC specific phenotype and their peculiar and immature molecular signature.
Human circulating fibrocytes
   In the early 90s, applying murine wound healing model Bucala et al. identified and isolated a blood-borne fibroblast-like cells, named fibrocytes \cite{Bucala1994}. Similarly to MOMCs, fibrocytes are isolated from peripheral blood mononuclear cells by culture in DMEM supplemented with 20% of FBS on fibronectin-coated plastics, and later on their mesengenic potential has been demonstrated in vitro and in vivo \cite{Hong_2005,Hong_2007}. Phenotype of these cells shows a great overlap with MOMCs and PCMO phenotypes, fibrocytes bear features of both fibroblast and monocytes expressing CD34, CD45 and CD11 as well as type I and type III collagen. Moreover, it has been also demonstrated that fibrocytes could be generated from CD14-positive enriched fraction of PB-MNCs \cite{Abe2001}, and in particular from the CD11b+CD115+Gr1+ sub-population of monocytes \cite{Niedermeier2009}.  Respect to MOMCs and PCMO fibrocytes attract great interest, maybe due their earliest identification, and these cells have been shown to have a role in different tissue fibrosis both in experimental and clinical settings \cite{Herzog_2010}. The bone marrow origin of fibrocytes has been definitively demonstrated by sex-mismatched or GFP-tagged bone marrow transplantation in mice. In these studies, after reconstitution of male bone marrow in female hosts, or engraftment of GFP-tagged transplant, the isolated fibrocytes from PB-MNCs and wounded tissue showed respectively positive hybridization to the Y chromosomes specific probe or GFP fluorescence emission \cite{Quan_2004,Mori2005}. However, the frequency of circulating cells showing fibrocyte-related phenotype are very low, from 0.1 to 0.5% of white blood cells \cite{Metz_2003} but optimized culture conditions could lead to 1-log fold higher culture yields \cite{Pilling_2009}. Even if not yet rigorously discussed due to the lack of sorting experiments, the previously reported possibility to obtain fibrocytes from CD14-positive circulating monocytes seems to support the idea of "differentiation" from circulating monocytes as the origin of ex vivo fibrocytes . However, phenotypic and functional feature of these cells, like growing dim of CD14 expression, induction of CD34 and acquisition of multilineage differentiation potential support more the hypothesis of a "de-differentiation", similarly to what proposed for MOMCs and PCMO.
Monoosteophils
Zhang and Shively in 2010, described a further bone forming cell population isolated in vitro from the circulating CD14-positive fraction and called them monoosteophils \cite{Zhang_2010}. Authors showed that culturing human circulating monocytes in RPMI-1640 supplemented with 10% FBS and LL-37, the active product of the proteolysis of the cathelicidin hCAP-18, forms large adherent macrophage-like cells distinct from M1, M2-polarized macrophages and dendritic cells. Monoosteophils show very close similarities with MPC-like phenotype characterized by the weak expression of CD14 and CD45, the absence of both CD34 and CD90, producing high level of osteopontin (SPP1) and  matrix metallopeptidase 7 and 9 (MMP-7, MMP-9) \cite{Pacini2010,Zhang_2013}. Monoosteophils has been demonstrated to be able of bone formation both in vitro and in vivo, as well as accelerating process of bone repair in murine models. Due to the limited amount of data regarding monoosteophils differentiation, a genuine mesengenic potential has not be demonstrated. However, the epiphyseal-like structure reported in ectopic monoosteophils-HA/TCP implants suggests that these cells could retain a wider mesengenic potential. Monoosteophils has been discussed as distinct from MOMC, fibrocytes or MCCs, descibed in the next paragraph, however this statement is based only on the different expression levels of CD14 and CD34. Once again, the generation of monoosteophils has been proposed as monocytes differentiation pathway alternative to the M1, M2 polarization or DC and osteoclast maturation. Nonetheless, the acquisition of the multiple differentiating potential toward non-phagocytic cell lineage as a consequence of a "de-differentiation" process should not be excluded, as the pluripotency-associated molecular signature has not been yet investigated.
Myeloid Calcifying Cells (MCCs)
    In 2005, Eghbali-Fatourechi et al.  describing from 1% to 2% of circulating osteoblast-like cells in PB-MNCs of adults and even at higher percentage in adolescents. These cells were detected and sorted for the expression of osteocalcin (OC) and bone alkaline phosphatase (BAP), demonstrating an osteogenic potential both in vitro and in vivo \cite{Eghbali-Fatourechi2005}. Similarly to MOMCs and fibrocytes, circulating OC+BAP+ cells can be cultured in 15% FBS containing media on fibronectin-coated plastics, but at the time of this first observation their origin was unclear. Later on, Fadini et al. showed that OC+BAP+ cells originate from the myeloid lineage and expressing monocyte/macrophage markers as CD45, CD14 and CD68, thus Authors renamed these cells as myeloid calcifying cells (MCCs) \cite{Fadini_2011}. MCCs are around 10-fold enriched in bone marrow than in peripheral blood. Moreover, in sex mismatched bone marrow transplantation, it has been demonstrated that these cells are resistant to myeloablation and long-lived. Due to the lack of CD34, MCCs has been described distinct from fibrocytes and MOMCs, while greatest similarities were reported respect to the CD34-negative monoosteophils, which also express OC but not BAP. 
 
stout TAM 2009
matsumoto epc 2006 2008
BM resident mac
Multi-nucleated Giant Cells (MNGCs)