F on ie s in Physiology | www. on ie sin.o g 1 Janua y 2021 | Volume 11 | A icle 583191
MINI REVIEW
published: 20 Janua y 2021
doi: 10.3389/ phys.2020.583191
Edi ed by:
Geo ge G an ,
Uni e si y o Abe deen,
Uni edKingdom
Re iewed by:
Meijing Wang,
Indiana Uni e si y Blooming on
School o Medicine,
Uni edS a es
Riikka Ki elä,
Uni e si y o Helsinki, Finland
*Co espondence:
Sand ina Nób ega-Pe ei a
[email p o ec ed]
B uno Be na des de Jesus
[email p o ec ed]
†These au ho s ha e con ibu ed
equally o his wo k and sha e i s
au ho ship
Special y sec ion:
This a icle was submi ed o
Clinical and T ansla ional Physiology,
a sec ion o he jou nal
F on ie s in Physiology
Recei ed: 14 July 2020
Accep ed: 16 Decembe 2020
Published: 20 Janua y 2021
Ci a ion:
San os F, Co eia M,
Nób ega-Pe ei a S and
Be na des de Jesus B (2021)
Age-Rela ed Pa hways in Ca diac
Regene a ion: A Role o lncRNAs?
F on . Physiol. 11:583191.
doi: 10.3389/ phys.2020.583191
Age-Rela ed Pa hways in Ca diac
Regene a ion: A Role o lncRNAs?
F anciscoSan os
1†, MagdaCo eia
1†, Sand inaNób ega-Pe ei a
1,2* and
B uno Be na des deJesus
1
*
1 Depa men o Medical Sciences and Ins i u e o Biomedicine- iBiMED, Uni e si y o A ei o, A ei o, Po ugal, 2 Faculdade
de Medicina, Ins i u o de Medicina Molecula João Lobo An unes, Uni e sidade de Lisboa, Lisboa, Po ugal
Aging imposes a ba ie o issue egene a ion. In he hea , aging leads o a se e e
ea angemen o he ca diac s uc u e and unc ion and o a subsequen inc eased isk
o hea ailu e. An in ica e ne wo k o dis inc pa hways con ibu es o age- ela ed
al e a ions du ing heal hy hea aging and accoun o a highe suscep ibili y o hea
disease. Ou unde s anding o he sys emic aging p ocess has al eady led o he design
o an i-aging s a egies o o he adop ion o p o ec i e in e en ions. Ne e heless, ou
unde s anding o he molecula de e minan s ope a ing du ing ca diac aging o epai
emains limi ed. He e, wewill summa ize he molecula and physiological al e a ions ha
occu du ing aging o he hea , highligh ing he po en ial ole o long non-coding RNAs
(lncRNAs) as no el and aluable a ge s in ca diac egene a ion/ epai .
Keywo ds: lncRNAs, hea , egene a ion, ep og amming, ansdi e en ia ion
INTRODUCTION
Wo ldwide, ca dio ascula diseases a e he leading cause o dea h, causing nea ly 18million
dea hs in 2017. Ca dio ascula diseases comp ise se e al pa hological condi ions, including
hea ailu e (Yusu e  al., 2001; Lloyd-Jones e  al., 2009, 2010; Mensah e  al., 2019). Aging
is p obably he mos impo an isk ac o o hea ailu e (Li e  al., 2020a). As opposed
o he neona al hea , adul mammalian hea s lose hei capaci y o ully egene a e a e
an exogenous o endogenous ha m (Lam and Sadek, 2018). This may be media ed h ough
se e al in e connec ed p ocesses, including cellula senescence and sec e ed ac o s, elome e
a i ion, mi ochond ial damage, cell dea h, o in lamma ion ( o a comp ehensi e e iew
on age- ela ed pa hways a ec ing he hea , see Li e al., 2020a). Al hough a pa ial myocy e
u no e has been obse ed in adul hea a e damage (e.g., myoca dial in a c ion), i
only pa ially and sligh ly es o es hea unc ion. Fo ins ance, i has been ecen ly
demons a ed ha manipula ion o elome e leng h h ough he exp ession o elome ase,
whose exp ession is silenced in he mouse hea om day 5 o 7 (Blasco e  al., 1995;
Bo ges and Liew, 1997; Richa dson e  al., 2012), may be bene icial in hea healing and
heal hspan (Be na des de Jesus and Blasco, 2011; Ba e  al., 2014).
Long non-coding RNAs (lncRNAs) ha e eme ged as impo an egula o s o epigene ic
modula ion and gene exp ession. Al hough dep i ed om coding po en ial, lncRNAs ha e
been associa ed wi h se e al biological p ocesses, including dosage compensa ion, genomic
imp in ing, aging, and cell di e en ia ion (Me ce e  al., 2009; Rinn and Chang, 2012;
Sousa-F anco e  al., 2019; Yao e  al., 2019). Fu he mo e, lncRNAs ha e been linked o
se e al diseases including ca dio ascula diseases (Hobuß e  al., 2019; Abbas e  al., 2020).
San os e al. Unde s anding Neona al Hea Regene a i e Po en ial
F on ie s in Physiology | www. on ie sin.o g 2 Janua y 2021 | Volume 11 | A icle 583191
In his e iew, wewill discuss he ca diac egene a ion p ope ies
o neona al and adul hea s. We will ocus on lncRNAs and
hei po en ial ole in ca diac egene a ion b ie ly discussing
he po en ial o ib oblas s as a sou ce o ca diomyocy es o
egene a i e medicine pu poses.
CARDIAC REGENERATION IN
NEONATAL AND ADULT HEARTS
The e is a gene al consensus on he capaci y o neona al hea s
o egene a e, a e dis inc ypes o damage (Supplemen a y
Figu e 1 – Po ello e  al., 2011, 2013; Haubne e  al., 2012,
2016; Jes y e  al., 2012; Mahmoud e  al., 2013, 2014, 2015;
Rubin e  al., 2013; Ande sen e  al., 2014, 2016; Au o a e  al.,
2014; Sadek e  al., 2014; B yan e  al., 2015; Da ehze eshki
e  al., 2015; Han e  al., 2015; Jiang e al., 2015; Kon ino e  al.,
2015; Aix e  al., 2016; Blom e  al., 2016; Kang e  al., 2016;
Tao e  al., 2016; Valien e-Alandi e  al., 2016; Xiong and Hou,
2016; Yu e al., 2016; Ai e al., 2017; Bassa e al., 2017; Malek
Mohammadi e al., 2017; Zeb owski e al., 2017; Ahmed e al.,
2018; Ingason e  al., 2018; Sampaio-Pin o e  al., 2018; Se e i
e  al., 2018; Cai e  al., 2019; Elhelaly e  al., 2019; Wang e  al.,
2019b; Fan e  al., 2020; Pei e  al., 2020; Li e  al., 2020b,
2020c). A comp ehensi e o e iew o neona al hea
egene a ion s udies has been p e iously and elegan ly de ailed
by Lam and Sadek (2018). Hea egene a ion seems o
be dependen on he ype o inju y ha causes loss o
ca diomyocy es. Fo example, c yoinju y does no induce he
same le el o egene a ion as apical esec ion o myoca dial
in a c ion. Fu he mo e, i is likely ha neona al hea
egene a ion is media ed by he p oli e a ion o p e-exis ing
ca diomyocy es, and no by ca diac s em o p ogeni o cells.
This egene a i e s a e occu s in an ex emely sho ime
ame (<10days; Eschenhagen e  al., 2017) and, jus a ew
days a e bi h, ca diomyocy es exi he cell cycle esul ing
in a decline in hea egene a ion capaci y. This is accompanied
by o he al e a ions in he ca diomyocy es, including hei
me abolic needs o changes in he exp ession o bo h coding
and non-coding genes. Subsequen ly, se e al s a egies ha e
been designed o egene a ing he adul hea . Those
app oaches may include he o ced e-en e ing in he cell
cycle o he p e-exis ing ca diomyocy es, o may include cell
ansdi e en ia ion s a egies, in which soma ic cells can
be con e ed in o unc ional ca diomyocy es o cell
eplacemen he apy (Qian e  al., 2012; Addis and Eps ein,
2013; Nam e  al., 2013; Wada e  al., 2013; Ghi oldi e  al.,
2017; Amin e  al., 2018; Engel and A dehali, 2018a).
A ROLE FOR lncRNAs IN HEART
REGENERATION
The impo ance o lncRNAs in hea egene a ion has been
b ough o ligh ecen ly (Ba e  al., 2016; Abbas e al., 2020).
LncRNAs a e a as ca ego y o non-coding, poo ly conse ed,
and issue- and de elopmen al s age-speci ic ansc ip s wi h
dis inc unc ions in se e al biological p ocesses, including
epigene ic, ansc ip ional, and pos - ansc ip ional egula ion.
Rega ding he ole o lncRNAs in hea egene a ion, we will
discuss some ecen s udies desc ibing lncRNAs di ec ly ac ing
(p omo ing o inhibi ing) on hea egene a ion (Table 1).
LncRNAs Tha P omo e Ca diomyocy e
P oli e a ion and Ca diac Regene a ion
P7 mice subjec ed o LAD liga ion and injec ed wi h adeno i us
con aining NR_045363 exhibi ed imp o ed le en icula ejec ion
ac ion and educed in a c size compa ed o he con ol-injec ed
g oup (Wang e  al., 2019a). Mice o e exp essing NR_045363
showed highe exp ession o ca diomyocy e mi o ic ma ke s,
such as Ki67 and phospho yla ed his one H3 (pH3), sugges ing
ha imp o ed hea unc ion a e MI was due o ca diomyocy e
p oli e a ion. The au ho s epo ed ha NR_045363 ac ed as a
compe ing endogenous RNA (ceRNA), binding o miR-216a
(Wang e al., 2019a). miR-216a is known o ep ess JAK2, leading
o dec eased le els o phospho yla ion o STAT3 (Hou e  al.,
2015). Fu he mo e, dele ion o STAT3 was shown o impai
ca diomyocy e p oli e a ion a e apical esec ion (Ku di e  al.,
2018), sugges ing ha NR_045363 p omo ed ca diomyocy e
p oli e a ion by modula ing he JAK2-STAT3 pa hway. So, he
absence o NR_045363 (which esul s in an up egula ion o
miR216a) led o educed ac i i y o he JAK2-STAT3, whils
NR_045363 o e exp ession (which leads o a down egula ion
o miR-216a) esul ed in an inc ease o he phospho yla ion
TABLE1 | LncRNAs wi h epo ed oles in ca diac egene a ion..
LncRNA Repo ed ole in ca diac egene a ion Re e ence
Nega i e egula o s
AZIN2-s
↓ ca diomyocy e p oli e a ion by
seques e ing miR-214 and leading o a
dec ease in he phospho yla ion o Ak
and Cyclin D
Li e al., 2018b
CAREL
↓ ca diomyocy e p oli e a ion by
seques e ing miR-296 and ac i a ing
T p53inp1 and I m2a
Cai e al., 2018
CPR
↓ ca diomyocy e p oli e a ion by he
ec ui men o DNMT3A, leading o
inc eased le els o me hyla ion o he
MCM3 p omo e
Ponnusamy e al.,
2019
CRRL
↓ ca diomyocy e p oli e a ion by
seques e ing miR-199a-3p, leading o an
inc eased exp ession o Hopx
Chen e al., 2018
LncDACH1 ↓ ca diomyocy e p oli e a ion by
egula ing PP1A/YAP1 signaling Cai e al., 2020a
SARRAH ↑ ca diomyocy e apop osis by inc easing
caspase ac i i y
T embinski e al.,
2020
Posi i e egula o s
NR_045363
↑ ca diomyocy e p oli e a ion ia he miR-
216a/JAK-STAT3 pa hway Wang e al., 2019a;
Chen e al., 2020↓ ca diomyocy e apop osis by blocking
p53 ac i a ion
ECRAR
↑ ca diomyocy e p oli e a ion by
p omo ing phospho yla ion o ERK1/2 o
ac i a e Cyclins D1 and E1
Chen e al., 2019
Si 1 an isense
lncRNA
↑ ca diomyocy e p oli e a ion and ↓
ca diomyocy e apop osis by s abilizing
Si 1
Li e al., 2018a
San os e al. Unde s anding Neona al Hea Regene a i e Po en ial
F on ie s in Physiology | www. on ie sin.o g 3 Janua y 2021 | Volume 11 | A icle 583191
le els o JAK2 and STAT3, hus p omo ing ca diomyocy e
p oli e a ion (Wang e  al., 2019a). Mo e ecen ly, NR_045363
was associa ed wi h ca diomyocy e apop osis. Chen e al. (2020)
epo ed ha loss o NR_045363 led o he ac i a ion o he
p53 signaling pa hway, p omo ing apop osis. On he o he hand,
o e exp essing NR_045363 inhibi ed apop osis and imp o ed
ca diac unc ion a e MI, hus po en ially media ing he ca diac
unc ions obse ed a e NR_045363 modula ion.
Long non-coding RNA endogenous ca diac egene a ion-
associa ed egula o (ECRAR) was ound o be up egula ed in
he e al hea , and i s exp ession g adually dec eased in pos na al
hea s. O e exp ession o ECRAR in pos na al a ca diomyocy es,
bo h in i o and in i o, esul ed in an inc ease o DNA
syn hesis, and an inc ease o cy okinesis (pH3 and au o a B
kinase), sugges ing a di ec in ol emen in ca diomyocy es
p oli e a ion (Chen e  al., 2019). O e exp ession o ECRAR
esul ed in he phospho yla ion o ERK1/2, hei subsequen
ansloca ion o he nucleus and he ansc ip ion o cell
p oli e a ion and cell cycle- ela ed genes (Chen e  al., 2019).
Li e  al. (2018a) iden i ied Si 1 an isense lncRNA (Si 1-as),
whose exp ession was high du ing hea de elopmen .
O e exp ession o his lncRNA esul ed in an inc ease o Ki67-
and pH3-posi i e ca diomyocy es. On he o he hand, silencing
o Si 1-as, bo h in i o and in i o, led o a dec ease o Ki67-
and pH3-posi i e ca diomyocy es, indica ing a po en ial decline
in cell di ision (Li e  al., 2018a). Fu he mo e, o e exp ession
o Si 1-as a e MI in adul mice esul ed in an inc eased exp ession
o cell-cycle speci ic ac o s Ki67 and pH3, hus sugges ing a
po en ial implica ion in ca diac heal h (Li e  al., 2018a).
Mo e ecen ly, Wilson e  al. (2020) desc ibed BANCR, a
lncRNA exclusi ely exp essed in p ima e e al ca diomyocy es.
BANCR p omo es ca diomyocy e mig a ion in i o and
en icula enla gemen in i o. To elucida e he egula ion o
BANCR in ca diomyocy es, he au ho s sugges ed ha TBX5
binding was esponsible o he e al hea -speci ic exp ession
o BANCR. Addi ionally, he au ho s iden i ied TEAD4 and
YAP1 ( wo ac o s in ol ed in he HIPPO pa hway) in he
same enhance , p omo ing BANCR exp ession. Finally, he
au ho s iden i ied a ole o BANCR in hea disease,
demons a ing highe exp ession in pedia ic bu no adul
dila ed ca diomyopa hy (Nelakan i and Xiao, 2020; Wilson
e al., 2020). O he lncRNAs associa ed wi h aged hea s include
lncRNA H19 (down egula ed in aged o ischemic hea ; Ho mann
e al., 2019), and MALAT1 a lncRNA which, i sel , is egula ed
by an an isense lncRNA ansc ip (TALAM1; Zong e  al.,
2016; Gomes e  al., 2019), was also shown o be dec eased
in aged hea s (Bink e  al., 2019; Gomes e  al., 2019), and
his dec ease was shown o bein ol ed in ca diac dys unc ion
(Zhu e  al., 2019; Li e  al., 2020a).
LncRNAs Tha Inhibi Ca diomyocy e
P oli e a ion and Ca diac Regene a ion
Cai e  al. (2018) explo ed he ole o lncRNAs du ing hea
egene a ion a e ischemic inju y, in bo h neona al and adul
mice. CAREL, a lncRNA whose exp ession g adually inc eased
in he neona al hea s om P1 o P10 mice, wi h P7 co esponding
o he ime poin a which he hea egene a i e capaci y is
los in mice (Cai e  al., 2018). Ca diac-speci ic o e exp ession
o CAREL led o a dec ease o ca diomyocy e p oli e a ion and
educed hea egene a ion in neona al mice a e inju y. On
he con a y, silencing CAREL p omo ed ca diac egene a ion
and imp o ed hea unc ional pa ame e s a e myoca dial
in a c ion in neona al and adul mice (Cai e al., 2018). CAREL
was ound o bea ceRNA, seques e ing miR-296. I was sugges ed
ha he CAREL-miR-296 in e ac ion led o he ac i a ion o
T p53inp1 and I m2a, leading o a dec ease in ca diomyocy e
p oli e a ion, hus esul ing in a educ ion o egene a ion.
In amyoca dial adminis a ion o CAREL o p1 neona al mice
inhibi ed ca diomyocy e mi osis and inc eased he o ma ion o
ca diac sca and, on he o he hand, o e exp ession o miR-256
p omo ed ca diomyocy e p oli e a ion and ca diac egene a ion
a e inju y. Simila ly, lncRNA ca diomyocy e p oli e a ion
egula o (CPR) was shown o be a nega i e egula o o
ca diomyocy e p oli e a ion and ca diac epai . Ponnusamy e al.
(2019) obse ed ha highe le els o CPR hampe ed ca diomyocy e
p oli e a ion, whils silencing CPR esul ed in ca diomyocy e
p oli e a ion in pos na al and adul hea s. CPR exp ession le els
we e ound o be highe in he adul hea , which is consis en
wi h hei lack o egene a ion. The au ho s epo ed ha CPR
ec ui s DNMT3A o se e al locus leading, in pa icula , o
inc eased le els o me hyla ion in he MCM3 p omo e (Ponnusamy
e  al., 2019). In di iding issues, MCM3 p omo es he ini ia ion
o DNA eplica ion and cell cycle p og ession (Lin e  al., 2008),
some hing hal ed by CPR in he hea and leading o he
inhibi ion o ca diomyocy es p oli e a ion.
Ano he lncRNA ha nega i ely egula es ca diac egene a ion
is LncDACH1. This lncRNA was ound o beg adually up egula ed
in pos na al hea s, which is in acco dance wi h he loss o
myoca dial egene a i e capaci y soon a e bi h (Cai e  al.,
2020). The au ho s sugges ha LncDACH1 binds p o ein
phospha ase 1 ca aly ic subuni alpha (PP1A), educing i s
dephospho yla ion capaci y, and inc eases he phospho yla ion
o yes-associa ed p o ein 1 (YAP1), p e en ing i s ansloca ion
o he nucleus and, hus, he ac i a ion o cell p oli e a ion-
ela ed genes ( on Gise e  al., 2012; Cai e  al., 2020). Ca diac-
speci ic o e exp ession o LncDACH1 esul ed in he supp ession
o neona al hea egene a ion and agg a a ion o ca diac unc ion
a e apical esec ion. These pheno ypes we e accompanied by
a dec ease in he numbe o ca diac-cells exp essing p oli e a i e
ma ke s (Cai e  al., 2020). Ca diomyocy e egene a ion- ela ed
lncRNA (CRRL) was also ound o be in ol ed in hea
egene a ion. CRRL silencing was associa ed wi h an inc eased
exp ession o EdU, Ki67, and pH3in P1 and P7 a ca diomyocy es
(Chen e  al., 2018). Simila esul s we e ob ained in neona al
a s pos -MI, concomi an ly wi h be e p ognosis such as educ ion
o he ib o ic leng h o he in a c wall and ib osis a ea in
he non-in a c zone. Ins ead, o e exp ession o CRRL leads o
a dec ease in pH3-posi i e ca diomyocy es and inhibi ion o
unc ional eco e y pos -MI. CRRL unc ion seemed o
be media ed h ough he binding o miR-199a-3p, esul ing in
an inc eased exp ession o Hopx, which is a nega i e egula o
o ca diomyocy e p oli e a ion (T i edi e  al., 2010).
LncRNA AZIN2-s , a splice a ian o he AZIN2 gene, was
ound o be up egula ed in human adul hea s. AZIN2-s was
San os e al. Unde s anding Neona al Hea Regene a i e Po en ial
F on ie s in Physiology | www. on ie sin.o g 4 Janua y 2021 | Volume 11 | A icle 583191
epo ed o nega i ely egula e ca diomyocy e p oli e a ion, bo h
in i o and in i o (Li e al., 2018b). O e exp ession o AZIN2-s
led o an an i-p oli e a i e pheno ype, ma ked by dec eased
le els o EdU-, Ki67-, pH3-, and Au o a-B. On he o he hand,
silencing AZIN2-s p omo ed ca diomyocy e p oli e a ion and
imp o ed ca diac unc ion a e MI. AZIN2-s seques e s
miR-214, leading o he elease o i s a ge PTEN, esul ing
in a dec ease in he phospho yla ion o Ak and Cyclin-D,
he e o e inhibi ing ca diomyocy e p oli e a ion. Reduced le els
o AZIN2-s allow miR-214 o ep ess PTEN, leading o
inc eased le els o phospho yla ed Ak and Cyclin-D1, hus
p omo ing ca diomyocy e p oli e a ion.
Mo e ecen ly, T embinski e  al. (2020) iden i ied lncRNA
SCOT1-an isense RNA egula ed du ing aging in he hea
(SARRAH), whose exp ession declines du ing aging. Inhibi ion
o Sa ah induces caspase ac i i y in mouse and human
ca diomyocy es, p omo ing apop osis. Gene se en ichmen analysis
a e SARRAH silencing showed en ichmen o apop osis- ela ed
pa hways, co obo a ing p e ious obse a ions (T embinski e al.,
2020). SARRAH was also ound o di ec ly bind o he p omo e s
h ough RNA-DNA iplex helix s uc u es, sugges ing ha i s
binding may ac i a e gene exp ession. Indeed, i was epo ed
ha SARRAH in e ac ed wi h ca diac ansc ip ion ac o cys eine-
ich p o ein 2 (CRIP2) and p300, which ace yla es his one H3
lysine 27 o ac i a e ansc ip ion (T embinski e  al., 2020). On
he o he hand, o e exp ession o SARRAH led o a dec ease
in caspase ac i i y. In adul mice a decline in apop osis was
obse ed a e o e exp essing SARRAH, sugges ing ha educed
exp ession le els o his lncRNA in aged mice migh con ibu e
o ca diomyocy e cell dea h in i o. Fu he mo e, educed le els
o Sa ah we e obse ed in he in a c ed and bo de egions
a e acu e MI (T embinski e  al., 2020).
Fu he mo e, se e al lncRNAs ha e been iden i ied as
p omo e s o ca diac ib osis (Liang e  al., 2018; Wang e  al.,
2018; Hao e  al., 2019; Zhang e  al., 2019a). Aged issues
accumula e signals ha p omo e he epi helial-mesenchymal
ansi ion (EMT), inducing he ansdi e en ia ion o epi helial
cells o mesenchymal cells, such as ib oblas s, which a e he
main media o s o ib osis h ough he deposi ion o ex acellula
ma ix. In he hea , many ib oblas s de i e om endo helial
cells, leading o excessi e deposi ion o ex acellula ma ix
and causing ca diac ib osis, which is common in pa ien s
wi h hea ailu e ( e iewed by San os e  al., 2019). Thus,
a ge ing hese lncRNAs may also beconside ed o imp o ing
hea unc ion.
REPROGRAMMING OF FIBROBLASTS
INTO CARDIOMYOCYTES AS A
POTENTIAL CELL REPLACEMENT
THERAPY – A ROLE FOR lncRNA
Cell ep og amming has eme ged as a no el s a egy o
egene a i e medicine and cell-based he apy. The ep og amming
o mouse and human ib oblas s in o induced plu ipo en s em
cells (iPSCs) using ansc ip ion ac o s (TFs) known o play
key oles in he main enance o emb yonic s em cell iden i y
sugges ed ha pa ien -de i ed iPSCs could be p oduced om
soma ic cells. This s a egy allowed he con e sion o ully
di e en ia ed cells in o cells wi h he po ency o bedi e en ia ed
in issues om di e en de elopmen lineages (Takahashi and
Yamanaka, 2006; Takahashi e al., 2007; Yamanaka, 2009; Abad
e al., 2013). Addi ionally, many o he ep og amming ba ie s,
such as he obs acles imposed by aging, ha e been add essed
h ough he di ec manipula ion o umo supp esso genes,
p53 o Ink4a/ARF (Li e  al., 2009; Ma ion e  al., 2009), o
he EMT-p omo ing ac o ZEB2 (Be na des de Jesus e  al.,
2018; San os e  al., 2019).
The ep og amming o ib oblas s in o iPSCs opened doo s
o di ec cell ep og amming. Di ec ca diac ep og amming o
ib oblas s in o ca diomyocy es [usually e med induced
ca diomyocy es (iCMs)] has eme ged as an a ac i e s a egy
o eplacing los o damaged cells in he hea . Mouse pos na al
ca diac and de mal ib oblas s ha e been ansdi e en ia ed in o
iCMs h ough he combined exp ession o h ee di e en ca diac-
speci ic TFs: Ga a4, Me 2c, and Tbx5 (GMT). The ec opic
exp ession o GMT ac i a es a ca diac-like gene exp ession
p og am and p omo es he con e sion o ib oblas s in o iCMs
(Ieda e al., 2010; Qian e al., 2012). Compa a i e gene exp ession
analyses epo ed ha iCMs gene a ed in i o exhibi ed bona
ide adul ca diomyocy e-like ea u es, such as a y acid oxida ion
o cell cycle exi (Mu aoka e al., 2019). Rema kably, his app oach
has been adap ed in i o, whe e ca diac ib oblas s ha e been
ansdi e en ia ed in o iCMs (Song e  al., 2012; Zhang e  al.,
2019b, 2019c), bypassing he need o e e ib oblas s o a
plu ipo en s a e (Liu e al., 2017; Mu aoka e al., 2019). Endogenous
ca diac ib oblas s comp ise abou 50% o all he cells in he
hea , making hem a po en ial sou ce o ca diomyocy es o
egene a i e he apy (Ieda e al., 2010). In ac , iCMs ep og ammed
om endogenous ca diac ib oblas s enhanced ca diac unc ion
a e myoca dial in a c ion, ully demons a ing he po en ial o
his s a egy o ca diac epai (Miyamo o e  al., 2018; Bek ik
and Fu, 2019; Lee e  al., 2020).
Despi e se e al encou aging esul s, cu en ep og amming
me hodologies emain somewha ine icien , as e y ew
ib oblas s a e ully con e ed in o unc ional iCMs. Di e en ial
exp ession pa e ns o lncRNAs ha e been obse ed in se e al
de elopmen al s ages, including ca diogenesis, and in ol e he
exp ession o lncRNAs B a ehea , Fend , and Ca men. In
ac , lncRNA ZEB2-NAT has been modula ed in o de o
imp o e he ep og amming o ib oblas s in o iPSCs (Be na des
de Jesus e al., 2018). Ha ing hese concep s in mind, i seems
easonable o expec ha modula ing lncRNAs migh imp o e
he e iciency o di ec ca diac ep og amming.
In i o The apeu ic Deli e y – Cu en
Issues
Rega ding phenocon e sion o ca diac cells, i is impo an o
men ion, howe e , ha many o he cu en p o ocols depend
on i al ec o s o gene deli e y. The e a e a ew sa e y issues
associa ed wi h he use o len i i al and e o i al ec o s, as
hey in eg a e hei genome in he hos cell. They could
po en ially dis u b endogenous gene exp ession and a e associa ed
San os e al. Unde s anding Neona al Hea Regene a i e Po en ial
F on ie s in Physiology | www. on ie sin.o g 5 Janua y 2021 | Volume 11 | A icle 583191
wi h he isk o inse ional mu agenesis, hampe ing he clinical
applica ion o his me hod. Howe e , non-in eg a i e i uses,
such as Sendai i us, and non- i al ep og amming sys ems
ha e eme ged as sa e al e na i es o clinical applica ion (Engel
and A dehali, 2018b; Miyamo o e  al., 2018; Tani e  al., 2018;
Chang e  al., 2019).
CONCLUSION
As p e iously discussed, se e al lncRNAs a e exp essed du ing
he de elopmen o he hea and du ing hea pa hologies.
Ta ge ing lncRNAs may be a no el s a egy agains hea
diseases (Ba e  al., 2016). Technically, he de elopmen o
speci ic and deli e able an isense ansc ip s (e.g.,
LNA-GapmeRs) has been p o ed powe ul and e icien ca ie s
o in i o a ge ing and RNase H-media ed deg ada ion o
speci ic a ge s (Be na des de Jesus e  al., 2018). Simila
app oaches may bedesigned o exp ession o selec ed lncRNAs,
down egula ed in ca diac diseases. We ha e o ace, howe e ,
ha mos human lncRNAs a e non-conse ed be ween species,
making i ex emely challenging o iden i y he unc ional
lncRNAs in i o. The lack o sequence conse a ion poses a
challenge o he ansla ional applica ion o human lncRNAs.
Since lncRNAs a e species-speci ic, weo en can only isualize
hei impac when s udied in hei speci ic sys em. This challenge
may only be add essed h ough a humanized expe imen al
model whe e he de ailed unc ion o non-conse ed lncRNAs
may be es ed. In conclusion, unde s and lncRNAs speci ic
p o iles in di iding s. non-di iding ca diomyocy es may allow
he de ec ion o po en ially d uggable a ge s o adul
hea epai .
AUTHOR CONTRIBUTIONS
FS, MC, SN-P, and BB planned, w o e, and discussed he pape .
SN-P and BB e ised he pape . All au ho s con ibu ed o
he a icle and app o ed he submi ed e sion.
FUNDING
This wo k was suppo ed by Fundação pa a a Ciência e Tecnologia
(FCT; ERA-CVD 2018 / 3599-PPCDT - ERA-CVD/0001/
2018 - INNOVATION).
SUPPLEMENTARY MATERIAL
The Supplemen a y Ma e ial o his a icle can be ound online
a : h ps://www. on ie sin.o g/a icles/10.3389/ phys.2020.583191/
ull#supplemen a y-ma e ial
Supplemen a y Figu e 1 | S udies on neona al hea egene a ion depic ing
di e en me hodologies. The s udies wi h blue backg ound obse ed hea
egene a ion whe he he s udies in ed could no de ec hea healing.
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